Cyclic amide derivatives as inhibitors of 11-β-hydroxysteroid dehydrogenase and uses thereof

ABSTRACT

The present invention relates amide compounds of formula (I): 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 1 , R 1a , Ar, A, B, W 1 , W 2 , D, a, b, and c are defined herein, and pharmaceutical acceptable salts thereof. These compounds have the ability to inhibit 11-β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) and which are therefore useful in the treatment of certain disorders that can be prevented or treated by inhibition of this enzyme. In addition the invention relates to the compounds, methods for their preparation, pharmaceutical compositions containing the compounds and the uses of these compounds in the treatment of certain disorders. It is expected that the compounds of the invention will find application in the treatment of conditions such as non-insulin dependent type 2 diabetes mellitus (NIDDM), insulin resistance, obesity, impaired fasting glucose, impaired glucose tolerance, lipid disorders such as dyslipidemia, hypertension and as well as other diseases and conditions.

FIELD OF THE INVENTION

The present invention relates to bicyclic heterocyclic amide derivativesthat have the ability to inhibit 11-β-hydroxysteroid dehydrogenase type1 (11β-HSD-1) and which are therefore useful in the treatment of certaindisorders that can be prevented or treated by inhibition of this enzyme.In addition the invention relates to the compounds, methods for theirpreparation, pharmaceutical compositions containing the compounds andthe uses of these compounds in the treatment of certain disorders. It isexpected that the compounds of the invention will find application inthe treatment of conditions such as non-insulin dependent type 2diabetes mellitus (NIDDM), insulin resistance, obesity, impaired fastingglucose, impaired glucose tolerance, lipid disorders such asdyslipidemia, hypertension and as well as other diseases and conditions.

BACKGROUND OF THE INVENTION

Glucocorticoids are stress hormones with regulatory effects oncarbohydrate, protein and lipid metabolism. Cortisol (or hydrocortisonein rodent) is the most important human glucocorticoid. 11-beta hydroxylsteroid dehydrogenase or 11 beta-HSD1 (11β-HSD-1) is a member of theshort chain dehydrogenase super-family of enzymes which convertsfunctionally inert cortisone to active cortisol locally, in apre-receptor manner. Given that the enzyme is abundantly expressed inmetabolically important tissues, such as adipose, muscle, and liver,that become resistant to insulin action in Type 2 Diabetes, inhibitionof 11β-HSD-1 offers the potential to restore the glucose lowering actionof insulin in these tissues without impacting the central HPA. Anotherimportant 11-beta hydroxyl steroid dehydrogenase, namely Type 211-beta-HSD (11β-HSD-2), which converts cortisol into cortisone, is aunidirectional dehydrogenase mainly located in kidney and protectsmineralocorticoid receptors from illicit activation by glucocorticoids.

Multiple lines of evidence indicate that 11β-HSD-1-mediatedintracellular cortisol production May have a pathogenic role in Obesity,Type 2 Diabetes and its co-morbidities.

In humans, treatment with non-specific inhibitor carbenoxolone improvesinsulin sensitivity in lean healthy volunteers and people with type 2diabetes (Walker B R et al (1995)). Likewise, 11β-HSD-1 activity wasdecreased in liver and increased in the adipose tissue of obeseindividuals. Similarly 11β-HSD-1 mRNA was found to be increased in bothvisceral and subcutaneous adipose tissue of obese patients (Desbriere Ret al (2006)) and was positively related to BMI and central obesity inPima Indians, Caucasians and Chinese youth (Lindsay R S et al (2003),Lee Z S et al (1999)). Adipose tissue 11β-HSD-1 and Hexose-6-PhosphateDehydrogenase gene expressions have also been shown to increase inpatients with type 2 diabetes mellitus (Uckaya G et al (2008)). In humanskeletal muscle 11β-HSD-1 expression was found to be positivelyassociated with insulin resistance (Whorwood C B et al (2002)).Increased 11β-HSD-1 expression was also seen in diabetic myotubes(Abdallah B M et al (2005)).

Various studies have been conducted in rodent models to substantiate therole of 11β-HSD-1 in diabetes and obesity. For example, over-expressionof 11β-HSD-1 specifically in adipose tissue causes development ofmetabolic syndrome (glucose intolerance, obesity, dyslipidemia andhypertension) in mice (Masuzaki H et al (2001)). Conversely, when11β-HSD-1 gene was knocked out, the resulting mice showed resistance todiet induced obesity and improvement of the accompanying dysregulationof glucose and lipid metabolism (Kotelevtsev Y et al (1997), Morton N Met al (2001), Morton N M et al (2004)). In addition, treatment ofdiabetic mouse models with specific inhibitors of 11β-HSD-1 caused adecrease in glucose output from the liver and overall increase ininsulin sensitivity (Alberts P et al (2003)).

The results of the preclinical and early clinical studies suggest thatthe treatment with a selective and potent inhibitor of 11β-HSD-1 will bean efficacious therapy for type 2 diabetes, obesity and metabolicsyndrome.

The role of 11β-HSD-1 as an important regulator of liver glucocorticoidlevel and thus of hepatic glucose production is well substantiated.Hepatic insulin sensitivity was improved in healthy human volunteerstreated with the non-specific 11β-HSD-1 inhibitor carbenoxolone (WalkerB R (1995)). Many in vitro and in vivo (animal model) studies showedthat the mRNA levels and activities of two key enzymes (PEPCK and G6PC)in gluconeogenesis and glycogenolysis were reduced by reducing 11β-HSD-1activity. Data from these models also confirm that inhibition of11β-HSD-1 will not cause hypoglycemia, as predicted since the basallevels of PEPCK and G6Pase are regulated independently ofglucocorticoids (Kotelevtsev Y (1997)).

In the pancreas cortisol is shown to inhibit glucose induced insulinsecretion as well as increase stress induced beta cell apoptosis.Inhibition of 11β-HSD-1 by carbenoxolone in isolated murine pancreaticbeta-cells improves glucose-stimulated insulin secretion (Davani B et al(2000)). Recently, it was shown that 11β-HSD-1 within alpha cellsregulates glucagon secretion and in addition may act in a paracrinemanner to limit insulin secretion from beta cells (Swali A et al(2008)). Levels of 11β-HSD-1 in islets from ob/ob mice were shown to bepositively regulated by glucocorticoids and were lowered by a selective11β-HSD-1 inhibitor and a glucocorticoid receptor antagonist. Increasedlevels of 11β-HSD-1 were associated with impaired GSIS (Ortsater H et al(2005)). In Zuker diabetic rats, troglitazone treatment improvedmetabolic abnormalities with a 40% decline in expression of 11β-HSD-1 inthe islets (Duplomb L et al (2004)). Cortisol inhibition may lead to anincrease in the insulin gene transcription and a normalization of firstphase insulin secretion (Shinozuka Y et al (2001)).

In human skeletal muscle 11β-HSD-1 expression is positively associatedinsulin resistance and increased expression of 11β-HSD-1 was alsoreported in type 2 diabetic myotubes (Abdallah B M et al (2005)).Recently the contribution of cortisol in muscle pathology is beingconsidered for modulating its action. Very recently it has beendemonstrated that targeted reduction or pharmacological inhibition of11β-HSD-1 in primary human skeletal muscle prevents the effect ofcortisone on glucose metabolism and palmitate oxidation (Salehzadeh F etal (2009)). Over activity of cortisol in muscle leads to muscle atrophy,fibre type switch and poor utilization of glucose due to insulinresistance. Cortisol might have a direct role in reducing muscle glucoseuptake.

Obesity is an important factor in Metabolic syndrome as well as in themajority (>80%) of type 2 diabetics, and omental (visceral) fat appearsto be of central importance. 11β-HSD-1 activity is increased in the bothvisceral and subcutaneous adipose tissue of obese individual (Lindsay RS et al (2003)). Cortisol activity in adipose is known to increase theadipogenic program. Inhibition of 11β-HSD-1 activity in pre-adipocyteshas been shown to decrease the rate of differentiation into adipocytes(Bader T et al (2002)). This is predicted to result in diminishedexpansion (possibly reduction) of the omental fat depot, i.e., reducedcentral obesity (Bujalska I J et al (1997) and (2006)). Intra-adiposecortisol levels have been associated with adipose hypertrophy,independent of obesity (Michailidou Z et al (2006)).

Cortisol in coordination with adrenergic signalling is also known toincrease lipolysis which leads to increase in plasma free fatty acidconcentrations which, in turn, is the primary cause of many deleteriouseffects of obesity (Tomlinson J W et al (2007)).

Adrenalectomy attenuates the effect of fasting to increase both foodintake and hypothalamic neuropeptide Y expression. This supports therole of glucocorticoids in promoting food intake and suggests thatinhibition of 11β-HSD-1 in the brain might increase satiety andtherefore reduce food intake (Woods S C (1998)). Inhibition of 11β-HSD-1by a small molecule inhibitor also decreased food intake and weight gainin diet induced obese mice (Wang S J Y et al (2006)).

The effects discussed above therefore suggest that an effective11β-NSD-1 inhibitor would have activity as an anti-obesity agent.

Cortisol in excess can also trigger triglyceride formation and VLDLsecretion in liver, which can contribute to hyperlipidemia andassociated dyslipidemia. It has been shown that 11β-HSD-1−/− transgenicmice have markedly lower plasma triglyceride levels and increased HDLcholesterol levels indicating a potential atheroprotective phenotype(Morton N M et al (2001)). In a diet-induced obese mouse model, anon-selective inhibitor of 11β-HSD-1 reduced plasma free fatty acid aswell as triacylglycerol (Wang S J et al (2006)). Over-expression of11β-HSD-1 in liver increased liver triglyceride and serum free fattyacids with the up regulation of hepatic lipogenic genes (Paterson J M etal (2004). It has been illustrated that inhibition of 11β-HSD-1 improvestriglyceridemia by reducing hepatic VLDL-TG secretion, with a shift inthe pattern of TG-derived fatty acid uptake toward oxidative tissues, inwhich lipid accumulation is prevented by increased lipid oxidation(Berthiaume M et al (2007)).

Atherosclerotic mouse model (APOE −/−) which are susceptible to atheromawhen fed high fat diet, are protected against development ofatherosclerosis when treated with 11β-HSD-1 inhibitors(Hermanowski-Vostaka A et al, (2005)).

Inhibition of 11β-HSD-1 in mature adipocytes is expected to attenuatesecretion of the plasminogen activator inhibitor 1 (PAI-1)—anindependent cardiovascular risk factor (Halleux C M et al (1999)).Furthermore, there is a clear correlation between glucocorticoidactivity and cardiovascular risk factor suggesting that a reduction ofthe glucocorticoid effects would be beneficial (Walker B R et al (1998),Fraser R et al (1999)).

The association between hypertension and insulin resistance might beexplained by increased activity of cortisol. Recent data show that theintensity of dermal vasoconstriction after topical application ofglucocorticoids is increased in patients with essential hypertension(Walker B R et al (1998)). Glucocorticoid was shown to increase theexpression of angiotensin receptor in vascular cell and thuspotentiating the renin-angiotensin pathway (Ullian M E et al (1996)),(Sato A et al (1994)). Role of cortisol in NO signalling and hencevasoconstriction has been proved recently (Liu Y et al (2009)). Thesefindings render 11β-HSD-1 a potential target for controllinghypertension and improving blood-flow in target tissues.

In the past decade, concern on glucocorticoid-induced osteoporosis hasincreased with the widespread use of exogenous glucocorticoids (GC).GC-induced osteoporosis is the most common and serious side-effect forpatients receiving GC. Loss of bone mineral density (BMD) is greatest inthe first few months of GC use. Mature bone-forming cells (osteoblasts)are considered to be the principal site of action of GC in the skeleton.The whole differentiation of mesenchymal stem cell toward the osteoblastlineage has been proven to be sensitive to GC as well as collagensynthesis (Kim C H et al (1999)). The effects of GC on this process aredifferent according to the stage of differentiation of bone cellprecursors. The presence of intact GC signalling is crucial for normalbone development and physiology, as opposed to the detrimental effect ofhigh dose exposure (Pierotti S et al (2008), Cooper M S et al (2000)).Other data suggest a role of 11β-HSD-1 in providing sufficiently highlevels of active glucocorticoid in osteoclasts, and thus in augmentingbone resorption (Cooper M S et al (2000)). The negative effect on bonenodule formation could be blocked by the non-specific inhibitorcarbenoxolone suggesting an important role of 11β-HSD-1 in theglucocorticoid effect (Bellows C G et al (1998)).

Stress and glucocorticoids influence cognitive function (de Quervain D Jet al (1998)). The enzyme 11β-HSD-1 controls the level of glucocorticoidaction in the brain also known to contributes to neurotoxicity (Rajan Vet al (1996)). It has been also suggested that inhibiting 11β-HSD-1 inthe brain may result in reduced anxiety (Tronche F et al (1999)). Thus,taken together, the hypothesis is that inhibition of 11β-HSD-1 in thehuman brain would prevent reactivation of cortisone into cortisol andprotect against deleterious glucocorticoid-mediated effects on neuronalsurvival and other aspects of neuronal function, including cognitiveimpairment, depression, and increased appetite.

Recent data suggest that the levels of the glucocorticoid targetreceptors and the 11β-HSD-1 enzymes determine the susceptibility toglaucoma (Stokes, J. et al. (2000)). Ingestion of carbenoxolone, anon-specific inhibitor of 11β-HSD-1, was shown to reduce the intraocularpressure by 20% in normal subjects. There are evidences that 11β-HSD-1isozyme may modulate steroid-regulated sodium transport across the NPE,thereby influencing intra ocular pressure (IOP). 11β-HSD-1 is suggestedto have a role in aqueous production, rather than drainage, but it ispresently unknown if this is by interfering with activation of theglucocorticoid or the mineralocorticoid receptor, or both (Rauz S et al(2001; 2003)).

The multitude of glucocorticoid action is exemplified in patients withprolonged increase in plasma glucocorticoids, so called “Cushing'ssyndrome”. These patients have prolonged increase in plasmaglucocorticoids and exhibit impaired glucose tolerance, type 2 diabetes,central obesity, and osteoporosis. These patients also have impairedwound healing and brittle skin. Administration of glucocorticoidreceptor agonist (RU38486) in Cushing's syndrome patients reverses thefeatures of metabolic syndrome (Neiman L K et al (1985)).

Glucocorticoids have been shown to increase risk of infection and delayhealing of open wounds. Patients treated with glucocorticoids have2-5-fold increased risk of complications when undergoing surgery.Glucocorticoids influence wound healing by interfering with productionor action of cytokines and growth factors like IGF, TGF-beta, EGF, KGFand PDGF (Beer H D et al (2000)). TGF-beta reverses theglucocorticoid-induced wound-healing deficit in rats by PDGF regulationin macrophages (Pierce G F et al (1989)). It has also been shown thatglucocorticoids decrease collagen synthesis in rat and mouse skin invivo and in rat and human fibroblasts (Oishi Y et al, 2002).

Glucocorticoids have also been implicated in conditions as diverseaspolycystic Ovaries Syndrome, infertility, memory dysfunction, sleepdisorders, myopathy (Endocrinology. 2011 January; 152(1):93-102. Epub2010 Nov. 24.PMID: 21106871) and muscular dystrophy. As such the abilityto target enzymes that have an impact on glucocorticoid levels isexpected to provide promise for the treatment of these conditions:

Based on patent literature and company press releases, there are manycompound tested for 11β-HSD-1 inhibition in the different stages of drugdiscovery pipeline.

Incyte Corporation's INCB13739 has proceeded furthest to phase IIb stageof clinical trial. The results of phase IIa trial for type 2 diabetes(28-days, placebo-controlled, two-step hyperinsulinemic clamp studies)showed that it was safe and well tolerated without any serious sideeffects and hypoglycemia.

Though this molecule significantly improved hepatic insulin sensitivitythere was no appreciable improvement in plasma glucose levels. Themolecule appeared to be having positive effects on risk factors forcardiovascular disease including reduction of LDL, total cholesterol andtriglycerides as well as more modest increases in HDL. INCB13739 iscurrently being studied in a dose ranging phase II b trials in T2Dpatients whose glucose levels are not controlled by metforminmonotherapy.

In the pre-clinical stage, Incyte's lead inhibitor INCB13739 was testedin rhesus monkey and was shown to inhibit adipose 11β-HSD-1 (INCB013739,a selective inhibitor of 11β-Hydroxysteroid Dehydrogenase Type 1(11βHSD1) improves insulin sensitivity and lowers plasma cholesterolover 28 days in patients with type 2 diabetes mellitus.

The evidence therefore strongly suggests that compounds that areinhibitors of 11β-Hydroxysteroid Dehydrogenase would be useful in thetreatment of a number of clinical conditions associated with theexpression of this enzyme. In addition it would be desirable if theinhibitors were selective inhibitors so as not to interfere with thefunctioning of closely related enzymes such as 11β-HSD-2 which is knownto provide a protective effect in the body.

OBJECTS OF INVENTION

The principal object of the invention is to provide compounds that areinhibitors of 11β-Hydroxysteroid Dehydrogenase. These compounds would beexpected to be useful in the treatment of 11β-HydroxysteroidDehydrogenase related conditions as discussed above.

A further object is to provide a pharmaceutical composition containing acompound that is an inhibitor of 11β-Hydroxysteroid Dehydrogenase and apharmaceutically acceptable excipient, diluent or carrier.

A further object is to provide a method of prevention or treatment of acondition associated with 11β-Hydroxysteroid Dehydrogenase activity in amammal.

STATEMENT OF INVENTION

The present invention provides compounds of Formula (I):

wherein:

each R¹ and R^(1a) is independently selected from the group consistingof H, halogen, OH, NO₂, CN, SH, NH₂, CF₃, OCF₃, optionally substitutedC₁-C₁₂alkyl, optionally substituted C₁-C₁₂haloalkyl optionallysubstituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl,optionally substituted C₂-C₁₂heteroalkyl, optionally substitutedC₃-C₁₂cycloalkyl, optionally substituted C₃-C₁₂cycloalkenyl, optionallysubstituted C₂-C₁₂heterocycloalkyl, optionally substitutedC₂-C₁₂heterocycloalkenyl, optionally substituted C₆-C₁₈aryl, optionallysubstituted C₁-C₁₈heteroaryl, optionally substituted C₁-C₁₂alkyloxy,optionally substituted C₂-C₁₂alkenyloxy, optionally substitutedC₂-C₁₂alkynyloxy, optionally substituted C₂-C₁₀heteroalkyloxy,optionally substituted C₃-C₁₂cycloalkyloxy, optionally substitutedC₃-C₁₂cycloalkenyloxy, optionally substituted C₂-C₁₂heterocycloalkyloxy,optionally substituted C₂-C₁₂ heterocycloalkenyloxy, optionallysubstituted C₆-C₁₈aryloxy, optionally substituted C₁-C₁₈heteroaryloxy,optionally substituted C₁-C₁₂alkylamino, SR², SO₃H, SO₂NR²R³, SO₂R²,SONR²R³, SOR², COR², COOH, COOR², CONR²R³, NR²COR³, NR²COOR³, NR²SO₂R³,NR²CONR²R³, NR²R³, and acyl, or any two R¹ on adjacent carbon atoms maybe joined to form a cyclic moiety, or any two R¹ on the same carbon whentaken together may form a group of the formula ═O or ═NR⁵, and the twoR^(1a) may be joined to form a double bond;

Ar is an optionally substituted C₁-C₁₈ heteroaryl group;

A is selected from the group consisting of S, SO, SO₂, O, and—CR^(a)R^(b)—;

B is a group of the formula —(CR^(c)R^(d))_(n)—;

wherein each R^(a), R^(b), R^(c) and R^(d) is independently selectedfrom the group consisting of H, halogen, OH, NO₂, CN, SH, NH₂, CF₃,OCF₃, optionally substituted C₁-C₁₂alkyl, optionally substitutedC₂-C₁₀heteroalkyl, optionally substituted C₁-C₁₂haloalkyl, optionallysubstituted C₃-C₁₂cycloalkyl, optionally substituted C₆-C₁₈aryl,optionally substituted C₁-C₁₈heteroaryl; SR², SO₃H, SO₂NR²R³, SO₂R²,SONR²R³, SOR², COR², COOH, COOR², CONR²R³, NR²COR³, NR²COOR³, NR²SO₂R³,NR²CONR²R³, NR²R³, and acyl,

or any two R^(a), R^(b), R^(c) and R^(d) on the same carbon atom whentaken together may form a cycloalkyl group or a substituent of theformula:

wherein each R² and R³ is independently selected from the groupconsisting of H, optionally substituted C₁-C₁₂alkyl, optionallysubstituted C₂-C₁₀heteroalkyl, optionally substituted C₁-C₁₂haloalkyl,optionally substituted C₃-C₁₂cycloalkyl, optionally substitutedC₆-C₁₈aryl, and optionally substituted C₁-C₁₈heteroaryl;

R⁴ is selected from the group consisting of O, S, and NR⁵;

R⁵ is selected from the group consisting of H, OR⁶, optionallysubstituted C₁-C₁₂alkyl, optionally substituted C₁-C₁₂haloalkyloptionally substituted C₂-C₁₂alkenyl, optionally substitutedC₂-C₁₂alkynyl, optionally substituted C₁-C₁₂alkyloxy, optionallysubstituted C₁-C₁₂haloalkyloxy, optionally substitutedC₂-C₁₀heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionallysubstituted C₃-C₁₂cycloalkenyl, optionally substituted C₂-C₁₂heterocycloalkyl, optionally substituted C₂-C₁₂ heterocycloalkenyl,optionally substituted C₆-C₁₈aryl, and optionally substitutedC₁-C₁₈heteroaryl,

R⁶ is selected from the group consisting of H, optionally substitutedC₁-C₁₂alkyl, optionally substituted C₂-C₁₀heteroalkyl, optionallysubstituted C₃-C₁₂cycloalkyl, optionally substituted C₆-C₁₈aryl, andoptionally substituted C₁-C₁₈heteroaryl,

or any two or more R^(a), R^(b), R^(c) and R^(d) may join together toform a multiple bond between adjacent carbon atoms such as a double ortriple bond, or a cyclic moiety connecting the carbon atoms to whichthey are attached;

W¹ and W² are selected such that one is N and the other is (CR¹ ₂),

the bond from the carbonyl carbon is joined to whichever of W¹ or W² isN;

-   -   D is O or (CR¹ ₂);    -   n is an integer selected from the group consisting of 0, 1, 2,        3, and 4;

a is an integer selected from the group consisting of 0, 1, and 2;

b is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5,6, 7, and 8,

c is an integer selected from 0, 1, and 2;

or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof.

As with any group of structurally related compounds which possess aparticular utility, certain embodiments of variables of the compounds ofthe Formula (I), are particularly useful in their end use application.

In some embodiments A is S. In some embodiments A is SO. In someembodiments A is SO₂. In some embodiments A is O. In some embodiments Ais CR^(a)R^(b).

In some embodiments R^(a) and R^(b) are each independently selected fromthe group consisting of H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, (CH₂)₃CH₃,Cl, Br, F, I, OH, NO₂, NH₂, CN, SO₃H, OCH₃, OCH₂CH₂CH₃, CF₃, and OCF₃.In some embodiments R^(a) is H. In some embodiments R^(b) is H. In someembodiments R^(a) and R^(b) are different such that the carbon is achiral carbon. In some embodiments one of R^(a) and R^(b) is H and theother is an optionally substituted alkyl.

B is a group of the formula —(CR^(c)R^(d))_(n)—. In some embodiments nis 0. In some embodiments n is 1. In some embodiments n is 2.

In some embodiments R^(e) and R^(d) are each independently selected fromthe group consisting of H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, (CH₂)₃CH₃,Cl, Br, F, I, OH, NO₂, NH₂, CN, SO₃H, OCH₃, OCH₂CH₂CH₃, CF₃, and OCF₃.In some embodiments both R^(c) and R^(d) are H such that B is CH₂.

In some embodiments any two or more R^(a), R^(b), R^(c) and R^(d) mayjoin together to form a multiple bond between adjacent carbon atoms suchas a double or triple bond, or a cyclic moiety connecting the carbonatoms to which they are attached.

In some embodiments two of R^(a), R^(b), R^(c) and R^(d) on adjacentcarbon atoms are joined to form a double bond. In some embodiments fourof R^(a), R^(b), R^(c) and R^(d) on adjacent carbon atoms are joined toform a triple bond.

In some embodiments one of R^(a) and R^(b) and one or R^(c) and R^(d)when taken together with the carbon atoms to which they are attachedform a cyclic moiety. Examples of cyclic moieties that may be formedinclude cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In some embodiments n=2 and one of R^(a) and R^(b) and one or R^(c) andR^(d) on the carbon atom two carbons removed (on the beta carbon) whentaken together with the carbon atoms to which they are attached and thealpha carbon atom form a cyclic moiety. Examples of cyclic moieties thatmay be formed include cyclobutyl, cyclopentyl and cyclohexyl.

In some embodiments A is CR^(a)R^(b) and B is CH₂, this providescompounds of formula

wherein R¹, R^(1a), R^(a), R^(b), Ar, W¹, W², D, a, b and c are asdefined above.

In some embodiments D is O. In some embodiments D is (CR¹ ₂).

In some embodiments A is CR^(a)R^(b), B is CH₂ and D is O, this providescompounds of formula (IIIa):

wherein R¹, R^(1a), R^(a), R^(b), Ar, W¹, W², a, b and c are as definedabove.

In some embodiments A is CR^(a)R^(b), B is CH₂ and D is (CR¹ ₂), thisprovides compounds of formula (IIIb):

wherein R¹, R^(1a), R^(a), R^(b), Ar, W¹, W², a, b and c are as definedabove.

In some embodiments c is O and the ring containing W¹ and W² is a 5membered ring. In some embodiments c is 1 and the ring containing W¹ andW² is a 6 membered ring. In some embodiments c is 2 and the ringcontaining W¹ and W² is a 7 membered ring.

In some embodiments A is CR^(a)R^(b), B is CH₂, D is O and c is 1, thisprovides compounds of formula (IVa):

wherein R¹, R^(1a), R^(a), Ar, W¹, W², a, and b are as defined above.

In some embodiments A is CR^(a)R^(b), B is CH₂, D is (CR¹ ₂) and c is 1,this provides compounds of formula (IVb):

wherein R¹, R^(1a), R^(a), R^(b), W¹, W², a and b are as defined above.

In some embodiments W¹ is N and W² is (CR¹ ₂). In some embodiments W¹ is(CR¹ ₂), and W² is N.

In some embodiments A is CR^(a)R^(b), B is CH₂, D is O, c is 1, W¹ is Nand W² is (CR¹ ₂). This provides compounds of formula (Va):

wherein R¹, R^(1a), R^(a), R^(b), Ar, a, and b are as defined above.

In some embodiments A is CR^(a)R^(b), B is CH₂, D is (CR¹ ₂), c is 1, W¹is N and W² is (CR¹ ₂), this provides compounds of formula (Vb).

wherein R¹, R^(1a), R^(a), R^(b), Ar, a and b are as defined above.

In some embodiments A is CR^(a)R^(b), B is CH₂, D is O, c is 1, W¹ is(CR¹ ₂), and W² is N this provides compounds of formula (Vc):

wherein R¹, R^(1a), R^(a), R^(b), Ar, a, and b are as defined above.

In some embodiments A is CR^(a)R^(b), B is CH₂, D is (CR¹ ₂), c is 1, W¹is N and W² is (CR¹ ₂), this provides compounds of formula (Vd).

wherein R¹, R^(1a), R^(a), R^(b), Ar, a and b are as defined above.

The group Ar may be any optionally substituted C₁-C₁₈ heteroaryl moiety.Suitable heteroaryl groups include thiophene, benzothiophene,benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole,naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine,pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine,pyridazine, tetrazole, indole, isoindole, 1H-indazole, purine,quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline,cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole,isothiazole, phenothiazine, oxazole, isooxazole, furazane, phenoxazine,pyridyl, quinolyl, isoquinolinyl, indolyl, and thienyl. In each instancewhere there is the possibility of multiple sites of substitution on theheteroaryl ring all possible attachment points are contemplated. Merelyby way of example if the heteroaryl is a pyridyl moiety it may be a2-pyridyly, a 3-pyridyl or a 4 pyridyl.

In some embodiments Ar is a group of the formula VI:

wherein each V¹, V², V³, V⁴, V⁵ and V⁶ is independently selected fromthe group consisting of N and CR⁷;

U is selected from the group consisting of NR⁸, O, S and CR⁸ ₂,

wherein each R⁷ is independently selected from the group consisting ofeach R³ is independently selected from the group consisting of H,halogen, OH, NO₂, CN, SH, NH₂, CF₃, OCF₃, optionally substitutedC₁-C₁₂alkyl, optionally substituted C₁-C₁₂haloalkyl, optionallysubstituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl,optionally substituted C₂-C₁₂heteroalkyl, optionally substitutedC₃-C₁₂cycloalkyl, optionally substituted C₃-C₁₂cycloalkenyl, optionallysubstituted C₂-C₁₂heterocycloalkyl, optionally substituted C₂-C₁₂heterocycloalkenyl, optionally substituted C₆-C₁₈aryl, optionallysubstituted C₁-C₁₈heteroaryl, optionally substituted C₁-C₁₂alkyloxy,optionally substituted C₂-C₁₂alkenyloxy, optionally substitutedC₂-C₁₂alkynyloxy, optionally substituted C₂-C₁₀heteroalkyloxy,optionally substituted C₃-C₁₂cycloalkyloxy, optionally substitutedC₃-C₁₂cycloalkenyloxy, optionally substituted C₂-C₁₂heterocycloalkyloxy, optionally substituted C₂-C₁₂heterocycloalkenyloxy, optionally substituted C₆-C₁₈aryloxy, optionallysubstituted C₁-C₁ heteroaryloxy, optionally substitutedC₁-C₁₂alkylamino, SR⁹, SO₃H, SO₂NR⁹R¹⁰, SO₂R⁹, SONR⁹R¹⁰, SOR⁹, COR⁹,COOH, COOR⁹, CONR⁹R¹⁰, NR⁹COR¹⁰, NR⁹COOR¹⁰, NR⁹SO₂R¹⁰, NR⁹CONR⁹R¹⁰,NR⁹R¹⁰, and acyl;

wherein R⁸ is selected from the group consisting of H, optionallysubstituted C₁-C₁₂alkyl, optionally substituted C₂-C₁₂alkenyl,optionally substituted C₂-C₁₂alkynyl, optionally substituted C₂-C₁₂heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionallysubstituted C₂-C₁₂heterocycloalkyl, optionally substituted C₆-C₁₈aryl,optionally substituted C₁-C₁₈heteroaryl, SO₃H, SO₂NR⁹R¹⁰, SO₂R⁹,SONR⁹R¹⁰, SOR⁹, COR⁹, COOH, COOR⁹, and CONR⁹R¹⁰;

wherein each R⁹ and R¹⁰ is independently selected from the groupconsisting of H, optionally substituted C₁-C₁₂alkyl, optionallysubstituted C₂-C₁₀heteroalkyl, optionally substituted C₁-C₁₂haloalkyl,optionally substituted C₃-C₁₂cycloalkyl, optionally substitutedC₆-C₁₈aryl, and optionally substituted C₁-C₁₈heteroaryl.

In some embodiments Ar is selected from the group consisting of:

wherein R⁷ is as defined above;

e is an integer selected from the group consisting of 0, 1, 2, 3 and 4;

f is an integer selected the group consisting of 0, 1, 2, and 3.

In some embodiments A is CR^(a)R^(b), B is CH₂, D is (CR¹ ₂), c is 1, W¹is N, W² is (CR¹ ₂) and Ar is a group of formula VIa, this providescompounds of formula (VIIa):

wherein R¹, R^(1a), R^(a), R^(b), R⁷, R⁸, a, b and e are as definedabove.

In some embodiments A is CR^(a)R^(b), B is CH₂, D is (CR¹ ₂), c is 1, W¹is N, W² is (CR¹ ₂) and Ar is a group of formula VIb, this providescompounds of formula (VIIb):

wherein R¹, R^(1a), R^(a), R^(b), R⁷, R⁸, a, b and f are as definedabove.

In some embodiments A is CR^(a)R^(b), B is CH₂, D is (CR¹ ₂), c is 1, W¹is N, W² is (CR¹ ₂) and Ar is a group of formula VIc, this providescompounds of formula (VIIc):

wherein R¹, R^(1a), R^(a), R^(b), R⁷, R⁸, a, b and e are as definedabove.

In some embodiments A is CR^(a)R^(b), B is CH₂, D is (CR¹ ₂), c is 1, W¹is N, W² is (CR¹ ₂) and Ar is a group of formula VId, this providescompounds of formula (VIId):

wherein R¹, R^(1a), R^(a), R^(b), R⁷, a, b and e are as defined above.

In some embodiments A is CR^(a)R^(b), B is CH₂, D is (CR¹ ₂), c is 1, W¹is N, W² is (CR¹ ₂) and Ar is a group of formula VIe, this providescompounds of formula (VIIe):

wherein R¹, R^(1a), R^(a), R^(b), R⁷, a, b and e are as defined above.

In some embodiments A is CR^(a)R^(b), B is CH₂, D is (CR¹ ₂), c is 1, W¹is N, W² is (CR¹ ₂) and Ar is a group of formula VIf, this providescompounds of formula (VIIf):

wherein R¹, R^(1a), R^(a), R^(b), R⁷, R⁸, a, b and e are as definedabove.

In some embodiments A is CR^(a)R^(b), B is CH₂, D is (CR¹ ₂), c is 1, W¹is N, W² is (CR¹ ₂) and Ar is a group of formula VIg, this providescompounds of formula (VIIg):

wherein R¹, R^(1a), R^(a), R^(b), R⁷, a, b and e are as defined above.

As can be seen many of the compounds of the present invention contain aquinoline or isoquinoline moiety as shown below. In order to assist thereader in determining substitution patterns on these moieties theaccepted ring atom numbering is shown below.

In some embodiments of the compounds described above R¹ is selected fromthe group consisting of H, methyl, CONHC(CH₃)₃, OH, CO₂H, CO₂CH₃,CO₂CH₂CH₃, phenyl, CH₂OH, CH₂CO₂H, CN and OCH₃. In some embodiments R¹is CO₂H.

In some embodiments a is 0. In some embodiments a is 1. In someembodiments a is 2. In some embodiments a is 3.

In some embodiments b is 0. In some embodiments b is 1. In someembodiments b is 2. In some embodiments b is 3. In some embodiments b is4. In some embodiments b is 5. In some embodiments b is 6. In someembodiments b is 7. In some embodiments b is 8.

In the compounds of the invention where there is a non H value for R¹,the substituent may be present on any available carbon atom. In someembodiments the substituent is located at the 4 position of theisoquinoline or quinoline ring. In some embodiments the substituent islocated at the 5 position of the the isoquinoline or quinoline ring.

In some embodiments of the compounds described above R^(1a) is selectedfrom the group consisting of H, methyl, CONHC(CH₃)₃, OH, CO₂H, CO₂CH₃,CO₂CH₂CH₃, phenyl, CH₂OH, CN and OCH₃.

In some embodiments of the compounds of the invention containing an R²group, the R² group is selected from H and C₁-C₁₂alkyl. In someembodiments R² is H. in some embodiments R² is methyl.

In some embodiments of the compounds of the invention containing an R³group, the R³ group is selected from H and C₁-C₁₂alkyl. In someembodiments R³ is H. in some embodiments R³ is methyl.

In some embodiments of the compounds of the invention containing an R⁴group, the R⁴ group is selected from O and S. In some embodiments R⁴ isO. in some embodiments R⁴ is S.

In some embodiments of the compounds of the invention containing an R⁵group, the R⁵ group is selected from H and C₁-C₁₂alkyl. In someembodiments R⁵ is H. in some embodiments R⁵ is methyl.

In some embodiments e is 1. In some embodiments e is 2. In someembodiments e is 3. In some embodiments e is 4. In circumstances where eis 1 the R⁷ group may be located at either the 4, 5, 6, or 7 position onthe six membered ring. In some embodiments where e is 1 the R⁷substituent is located at the 4 position on the ring. In someembodiments where e is 1 the R⁷ substituent is located at the 5 positionon the ring. In some embodiments where e is 1 the R⁷ substituent islocated at the 6 position on the ring. In some embodiments where e is 1the R⁷ substituent is located at the 7 position on the ring.

In some embodiments f is 1. In some embodiments f is 2. In someembodiments fi is 3. In some embodiments where f is 1 the R⁷ substituentis located at the 4 position on the ring. In some embodiments where f is1 the R⁷ substituent is located at the 5 position on the ring. In someembodiments where f is 1 the R⁷ substituent is located at the 6 positionon the ring. In some embodiments where f is 1 the R⁷ substituent islocated at the 7 position on the ring.

R⁷ may be selected from a wide range of possible substituents asdiscussed above. In some embodiments each R⁷ is independently selectedfrom the group consisting of H, halogen, OH, NO₂, CN, optionallysubstituted C₁-C₁₂alkyl, optionally substituted C₃-C₁₂cycloalkylC₁-C₁₂haloalkyl, optionally substituted, optionally substitutedC₆-C₁₈aryl, optionally substituted C₁-C₁₈heteroaryl, optionallysubstituted C₂-C₁₂heterocycloalkyloxy, C₁-C₁₂alkoxyl, andC₁-C₁₂haloalkoxyl. Exemplary R⁷ substituents include CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, (CH₂)₃CH₃, cyclopropyl, isopropoxy, I, Br, F, Cl,OH, NO₂, NH₂, CN, SO₃H, OCH₃, OCH₂CH₂CH₃, CF₃, OCF₃, thiophen-2-yl,5-fluoro-thiophen-2-yl, furan-2-yl, 5-methyl-furan-2-yl, pyridine-2-yl,3-fluoropyridine-2-yl, 3-methyl-isoxazol-5-yl, 3-fluoro-phenyl,4-fluoro-phenyl, 1-methyl pyroll-2-yl, 5-fluoro-furan-2-yl,5-cyano-furan-2-yl, and 5-carboxy-furan-2-yl.

R⁸ may be selected from a wide range of possible substituents asdiscussed above. In some embodiments each R⁸ is independently selectedfrom the group consisting of H, halogen, OH, NO₂, CN, C₁-C₁₂alkyl,C₁-C₁₂haloalkyl, C₁-C₁₂alkoxyl, and C₁-C₁₂haloalkoxyl. Exemplary R⁸substituents include CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, (CH₂)₃CH₃, I, Br,F, I, OH, NO₂, NH₂, CN, SO₃H, OCH₃, OCH₂CH₂CH₃, CF₃, and OCF₃.

Many if not all of the variables discussed above may be optionallysubstituted. If the variable is optionally substituted then in someembodiments each optional substituent is independently selected from thegroup consisting of halogen, ═O, ═S, —CN, —NO₂, —CF₃, —OCF₃, alkyl,alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl,cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl,heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl,arylalkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl,heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkyloxy,alkyloxyalkyl, alkyloxycycloalkyl, alkyloxyheterocycloalkyl,alkyloxyaryl, alkyloxyheteroaryl, alkyloxycarbonyl, alkylaminocarbonyl,alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy,heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy,heteroaryloxy, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl,arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl,arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl,aminosulfinylaminoalkyl, —C(═O)OH, —C(═O)R^(e), —C(═O)OR^(e),C(═O)NR^(e)R^(f), C(═NOH)R^(e), C(═NR^(e))NR^(f)R^(g), NR^(e)R^(f),NR^(e)C(═O)R^(f), NR^(e)C(═O)OR^(f), NR^(e)C(═O)NR^(f)R^(g),NR^(e)C(═NR^(f))NR^(g)R^(h), NR^(e)SO₂R^(f), —SR^(e), SO₂NR^(e)R^(f),—OR^(e), OC(═O)NR^(e)R^(f), OC(═O)R^(e) and acyl, wherein R^(e), R^(g)and R^(h) are each independently selected from the group consisting ofH, C₁-C₁₂alkyl, C₁-C₁₂haloalkyl, C₂-C₁₂alkenyl, C₂-C₁₂alkynyl,heteroalkyl, C₃-C₁₂cycloalkyl, C₃-C₁₂cycloalkenyl,C₁-C₁₂heterocycloalkyl, heterocycloalkenyl, C₆-C₁₂aryl,C₁-C₁₈heteroaryl, and acyl, or any two or more of R^(a), R^(b), R^(c)and R^(d), when taken together with the atoms to which they are attachedform a heterocyclic ring system with 3 to 12 ring atoms.

In some embodiments each optional substituent is independently selectedfrom the group consisting of: F, Cl, Br, ═O, ═S, —CN, —NO₂, alkyl,alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkylamino,aminoalkyl, acylamino, phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl,arylsulfonyl, aminosulfonyl, —C(O)OR^(a), COOH, SH, and acyl.

In some embodiments each optional substituent is independently selectedfrom the group consisting of: F, Br, Cl, ═O, ═S, —CN methyl,trifluoro-methyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, propyl,2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl,3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, pent-4-enyl,hexyl, heptyl, octyl, phenyl, NH₂, —NO₂, phenoxy, hydroxy, methoxy,trifluoro-methoxy, ethoxy, and methylenedioxy.

Alternatively, two optional substituents on the same moiety when takentogether may be joined to form a fused cyclic substituent attached tothe moiety that is optionally substituted. Accordingly the termoptionally substituted includes a fused ring such as a cycloalkyl ring,a heterocycloalkyl ring, an aryl ring or a heteroaryl ring.

In addition to compounds of formula I, the embodiments disclosed arealso directed to pharmaceutically acceptable salts, pharmaceuticallyacceptable N-oxides, pharmaceutically acceptable prodrugs, andpharmaceutically active metabolites of such compounds, andpharmaceutically acceptable salts of such metabolites.

The invention also relates to pharmaceutical compositions including acompound of the invention and a pharmaceutically acceptable carrier,diluent or excipient.

In a further aspect the present invention provides a method ofprevention or treatment of a condition in a mammal, the methodcomprising administering an effective amount of a compound of theinvention. In one embodiment the condition is a condition that can betreated by inhibition of 11β-HSD1.

In yet an even further aspect the invention provides the use of acompound of the invention in the preparation of a medicament for thetreatment of a condition in a mammal. In one embodiment the condition isa condition that can be treated by inhibition of 11β-HSD1.

In yet an even further aspect the invention provides the use of acompound of the invention in the treatment of a condition in a mammal.In one embodiment the condition is a condition that can be treated byinhibition of 11β-HSD1.

In some embodiments the condition is selected from the group consistingof is selected from the group consisting of diabetes, hyperglycemia, lowglucose tolerance, hyperinsulinemia, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, dyslipidemia, obesity,abdominal obesity, glaucoma, hypertension, atherosclerosis and itssequelae, retinopathy and other ocular disorders, nephropathy,neuropathy, myopathy, osteoporosis, osteoarthritis, dementia,depression, neurodegenerative disease, psychiatric disorders, Polycysticovaries syndrome, infertility, Cushing's Disease, Cushing's syndrome,viral diseases, and inflammatory diseases.

In some embodiments the condition is diabetes. In some embodiments thecondition is type II diabetes.

In some embodiments the compound is administered in combination with anadjuvant. In some embodiments the adjuvant is selected from the groupconsisting of dipeptidyl peptidase-IV (DP-IV) inhibitors; (b) insulinsensitizing agents; (c) insulin and insulin mimetics; (d) sulfonylureasand other insulin secretagogues; (e) alpha.-glucosidase inhibitors; (f)GLP-1, GLP-1 analogs, and GLP-1 receptor agonists; and combinationsthereof.

In one other embodiment the compound is administered as a substitute formonotherapy or combination therapy, in an event of failure of treatmentby agent selected from the group consisting of dipeptidyl peptidase-IV(DP-IV) inhibitors; (b) insulin sensitizing agents; (c) insulin andinsulin mimetics; (d) sulfonylureas and other insulin secretagogues; (e)alpha.-glucosidase inhibitors; (f) GLP-1, GLP-1 analogs, and GLP-1receptor agonists; and combinations thereof.

In one embodiment the insulin sensitizing agent is selected from thegroup consisting of (i) PPAR-gamma-agonists, (ii) PPAR-alpha-agonists,(iii) PPAR-alpha/gamma-dual agonists, (iv) biguanides, and combinationsthereof.

These and other teachings of the invention are set forth herein.

DETAILED DESCRIPTION OF THE INVENTION

In this specification a number of terms are used which are well known toa skilled addressee. Nevertheless for the purposes of clarity a numberof terms will be defined.

As used herein, the term “unsubstituted” means that there is nosubstituent or that the only substituents are hydrogen.

The term “optionally substituted” as used throughout the specificationdenotes that the group may or may not be further substituted or fused(so as to form a condensed polycyclic system), with one or morenon-hydrogen substituent groups. In certain embodiments the substituentgroups are one or more groups independently selected from the groupconsisting of halogen, ═O, ═S, —CN, —NO₂, —CF₃, —OCF₃, alkyl, alkenyl,alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl,cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl,cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl,heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkyloxy,alkyloxyalkyl, alkyloxycycloalkyl, alkyloxyheterocycloalkyl,alkyloxyaryl, alkyloxyheteroaryl, alkyloxycarbonyl, alkylaminocarbonyl,alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy,heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy,heteroaryloxy, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl,arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl,arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl,aminosulfinylaminoalkyl, —C(═O)OH, —C(═O)R^(e), —C(═O)OR^(e),C(═O)NR^(e)R^(f), C(═NOH)R^(e), C(═NR^(e))NR^(f)R^(g), NR^(e)R^(f),NR^(e)C(═O)R^(f), NR^(e)C(═O)OR^(f), NR^(e)C(═O)NR^(f)R^(g),NR^(e)C(═NR^(f))NR^(g)R^(h), NR^(e)SO₂R¹, —SR^(e), SO₂NR^(e)R^(f),—OR^(e), OC(═O)NR^(e)R^(f), OC(═O)R^(e) and acyl,

wherein R^(e), R^(f), R^(g) and R^(h) are each independently selectedfrom the group consisting of H, C₁-C₁₂haloalkyl, C₂-C₁₂alkenyl,C₂-C₁₂alkynyl, C₁-C₁₀heteroalkyl, C₃-C₁₂cycloalkyl, C₃-C₁₂cycloalkenyl,C₁-C₁₂heterocycloalkyl, C₁-C₁₂heterocycloalkenyl, C₆-C₁₈aryl,C₁-C₁₈heteroaryl, and acyl, or any two or more of R^(a), R^(b), R^(c)and R^(d), when taken together with the atoms to which they are attachedform a heterocyclic ring system with 3 to 12 ring atoms.

In some embodiments each optional substituent is independently selectedfrom the group consisting of: halogen, ═O, ═S, —CN, —NO₂, —CF₃, —OCF₃,alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkyloxy,alkyloxyalkyl, alkyloxyaryl, alkyloxyheteroaryl, alkenyloxy, alkynyloxy,cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy,heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl,heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl,arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl,aminoalkyl, —COOH, —SH, and acyl.

Examples of particularly suitable optional substituents include F, Cl,Br, I, CH₃, CH₂CH₃, OH, OCH₃, CF₃, OCF₃, NO₂, NH₂, and CN.

In the definitions of a number of substituents below it is stated that“the group may be a terminal group or a bridging group”. This isintended to signify that the use of the term is intended to encompassthe situation where the group is a linker between two other portions ofthe molecule as well as where it is a terminal moiety. Using the termalkyl as an example, some publications would use the term “alkylene” fora bridging group and hence in these other publications there is adistinction between the terms “alkyl” (terminal group) and “alkylene”(bridging group). In the present application no such distinction is madeand most groups may be either a bridging group or a terminal group.

“Acyl” means an R—C(═O)— group in which the R group may be an alkyl,cycloalkyl, heterocycloalkyl, aryl or heteroaryl group as definedherein. Examples of acyl include acetyl and benzoyl. The group may be aterminal group or a bridging group. If the group is a terminal group itis bonded to the remainder of the molecule through the carbonyl carbon.

“Acylamino” means an R—C(═O)—NH— group in which the R group may be analkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group as definedherein. The group may be a terminal group or a bridging group. If thegroup is a terminal group it is bonded to the remainder of the moleculethrough the nitrogen atom.

“Alkenyl” as a group or part of a group denotes an aliphatic hydrocarbongroup containing at least one carbon-carbon double bond and which may bestraight or branched preferably having 2-12 carbon atoms, morepreferably 2-10 carbon atoms, most preferably 2-6 carbon atoms, in thenormal chain. The group may contain a plurality of double bonds in thenormal chain and the orientation about each is independently E or Z. Thealkenyl group is preferably a 1-alkenyl group. Exemplary alkenyl groupsinclude, but are not limited to, ethenyl, propenyl, butenyl, pentenyl,hexenyl, heptenyl, octenyl and nonenyl. The group may be a terminalgroup or a bridging group.

“Alkenyloxy” refers to an alkenyl-O— group in which alkenyl is asdefined herein. Preferred alkenyloxy groups are C₁-C₆alkenyloxy groups.The group may be a terminal group or a bridging group. If the group is aterminal group it is bonded to the remainder of the molecule through theoxygen atom.

“Alkyl” as a group or part of a group refers to a straight or branchedaliphatic hydrocarbon group, preferably a C₁-C₁₂alkyl, more preferably aC₁-C₁₀alkyl, most preferably C₁-C₆ unless otherwise noted. Examples ofsuitable straight and branched C₁-C₆alkyl substituents include methyl,ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and thelike. The group may be a terminal group or a bridging group.

“Alkylamino” includes both mono-alkylamino and dialkylamino, unlessspecified. “Mono-alkylamino” means an Alkyl-NH— group, in which alkyl isas defined herein. “Dialkylamino” means a (alkyl)₂N— group, in whicheach alkyl may be the same or different and are each as defined hereinfor alkyl. The alkyl group is preferably a C₁-C₆alkyl group. The groupmay be a terminal group or a bridging group. If the group is a terminalgroup it is bonded to the remainder of the molecule through the nitrogenatom.

“Alkylaminocarbonyl” refers to a group of the formula(Alkyl)_(x)(H)_(y)NC(═O)— in which alkyl is as defined herein, x is 1 or2, and the sum of X+Y=2. The group may be a terminal group or a bridginggroup. If the group is a terminal group it is bonded to the remainder ofthe molecule through the carbonyl carbon.

“Alkyloxy” refers to an alkyl-O— group in which alkyl is as definedherein. Preferably the alkyloxy is a C₁-C₆alkyloxy. Examples include,but are not limited to, methoxy and ethoxy. The group may be a terminalgroup or a bridging group.

“Alkyloxyalkyl” refers to an alkyloxy-alkyl- group in which the alkyloxyand alkyl moieties are as defined herein. The group may be a terminalgroup or a bridging group. If the group is a terminal group it is bondedto the remainder of the molecule through the alkyl group.

“Alkyloxyaryl” refers to an alkyloxy-aryl- group in which the alkyloxyand aryl moieties are as defined herein. The group may be a terminalgroup or a bridging group. If the group is a terminal group it is bondedto the remainder of the molecule through the aryl group.

“Alkyloxycarbonyl” refers to an alkyl-O—C(═O)— group in which alkyl isas defined herein. The alkyl group is preferably a C₁-C₆ alkyl group.Examples include, but are not limited to, methoxycarbonyl andethoxycarbonyl. The group may be a terminal group or a bridging group.If the group is a terminal group it is bonded to the remainder of themolecule through the carbonyl carbon.

“Alkyloxycycloalkyl” refers to an alkyloxy-cycloalkyl- group in whichthe alkyloxy and cycloalkyl moieties are as defined herein. The groupmay be a terminal group or a bridging group. If the group is a terminalgroup it is bonded to the remainder of the molecule through thecycloalkyl group.

“Alkyloxyheteroaryl” refers to an alkyloxy-heteroaryl- group in whichthe alkyloxy and heteroaryl moieties are as defined herein. The groupmay be a terminal group or a bridging group. If the group is a terminalgroup it is bonded to the remainder of the molecule through theheteroaryl group.

“Alkyloxyheterocycloalkyl” refers to an alkyloxy-heterocycloalkyl- groupin which the alkyloxy and heterocycloalkyl moieties are as definedherein. The group may be a terminal group or a bridging group. If thegroup is a terminal group it is bonded to the remainder of the moleculethrough the heterocycloalkyl group.

“Alkylsulfinyl” means an alkyl-S—(═O)— group in which alkyl is asdefined herein. The alkyl group is preferably a C₁-C₆ alkyl group.Exemplary alkylsulfinyl groups include, but not limited to,methylsulfinyl and ethylsulfinyl. The group may be a terminal group or abridging group. If the group is a terminal group it is bonded to theremainder of the molecule through the sulfur atom.

“Alkylsulfonyl” refers to an alkyl-S(═O)₂— group in which alkyl is asdefined above. The alkyl group is preferably a C₁-C₆alkyl group.Examples include, but not limited to methylsulfonyl and ethylsulfonyl.The group may be a terminal group or a bridging group. If the group is aterminal group it is bonded to the remainder of the molecule through thesulfur atom.

“Alkynyl” as a group or part of a group means an aliphatic hydrocarbongroup containing a carbon-carbon triple bond and which may be straightor branched preferably having from 2-12 carbon atoms, more preferably2-10 carbon atoms, more preferably 2-6 carbon atoms in the normal chain.Exemplary structures include, but are not limited to, ethynyl andpropynyl. The group may be a terminal group or a bridging group.

“Alkynyloxy” refers to an alkynyl-O— group in which alkynyl is asdefined herein. Preferred alkynyloxy groups are C₁-C₆alkynyloxy groups.The group may be a terminal group or a bridging group. If the group is aterminal group it is bonded to the remainder of the molecule through theoxygen atom.

“Aminoalkyl” means an NH₂-alkyl- group in which the alkyl group is asdefined herein. The group may be a terminal group or a bridging group.If the group is a terminal group it is bonded to the remainder of themolecule through the alkyl group.

“Aminosulfonyl” means an NH₂—S(═O)₂— group. The group may be a terminalgroup or a bridging group. If the group is a terminal group it is bondedto the remainder of the molecule through the sulfur atom.

“Aryl” as a group or part of a group denotes (i) an optionallysubstituted monocyclic, or fused polycyclic, aromatic carbocycle (ringstructure having ring atoms that are all carbon) preferably having from5 to 12 atoms per ring. Examples of aryl groups include phenyl,naphthyl, and the like; (ii) an optionally substituted partiallysaturated bicyclic aromatic carbocyclic moiety in which a phenyl and aC₅₋₇ cycloalkyl or C₅₋₇ cycloalkenyl group are fused together to form acyclic structure, such as tetrahydronaphthyl, indenyl or indanyl. Thegroup may be a terminal group or a bridging group. Typically an arylgroup is a C₆-C₁₈ aryl group.

“Arylalkenyl” means an aryl-alkenyl- group in which the aryl and alkenylare as defined herein. Exemplary arylalkenyl groups include phenylallyl.The group may be a terminal group or a bridging group. If the group is aterminal group it is bonded to the remainder of the molecule through thealkenyl group.

“Arylalkyl” means an aryl-alkyl- group in which the aryl and alkylmoieties are as defined herein. Preferred arylalkyl groups contain aC₁₋₅alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl,1-naphthalenemethyl and 2-naphthalenemethyl. The group may be a terminalgroup or a bridging group. If the group is a terminal group it is bondedto the remainder of the molecule through the alkyl group.

“Arylalkyloxy” refers to an aryl-alkyl-O— group in which the alkyl andaryl are as defined herein. The group may be a terminal group or abridging group. If the group is a terminal group it is bonded to theremainder of the molecule through the oxygen atom.

“Arylamino” includes both mono-arylamino and di-arylamino unlessspecified. Mono-arylamino means a group of formula arylNH—, in whicharyl is as defined herein. Di-arylamino means a group of formula(aryl)₂N— where each aryl may be the same or different and are each asdefined herein for aryl. The group may be a terminal group or a bridginggroup. If the group is a terminal group it is bonded to the remainder ofthe molecule through the nitrogen atom.

“Arylheteroalkyl” means an aryl-heteroalkyl- group in which the aryl andheteroalkyl moieties are as defined herein. The group may be a terminalgroup or a bridging group. If the group is a terminal group it is bondedto the remainder of the molecule through the heteroalkyl group.

“Aryloxy” refers to an aryl-O— group in which the aryl is as definedherein. Preferably the aryloxy is a C₆-C₁₈aryloxy, more preferably aC₆-C₁₀aryloxy. The group may be a terminal group or a bridging group. Ifthe group is a terminal group it is bonded to the remainder of themolecule through the oxygen atom.

“Arylsulfonyl” means an aryl-S(═O)₂— group in which the aryl group is asdefined herein. The group may be a terminal group or a bridging group.If the group is a terminal group it is bonded to the remainder of themolecule through the sulfur atom.

A “bond” is a linkage between atoms in a compound or molecule. The bondmay be a single bond, a double bond, or a triple bond.

“Cycloalkenyl” means a non-aromatic monocyclic or multicyclic ringsystem containing at least one carbon-carbon double bond and preferablyhaving from 5-10 carbon atoms per ring. Exemplary monocycliccycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.The cycloalkenyl group may be substituted by one or more substituentgroups. A cycloalkenyl group typically is a C₃-C₁₂ alkenyl group. Thegroup may be a terminal group or a bridging group.

“Cycloalkyl” refers to a saturated monocyclic or fused or Spiropolycyclic, carbocycle preferably containing from 3 to 9 carbons perring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and thelike, unless otherwise specified. It includes monocyclic systems such ascyclopropyl and cyclohexyl, bicyclic systems such as decalin, andpolycyclic systems such as adamantane. A cycloalkyl group typically is aC₃-C₁₂ alkyl group. The group may be a terminal group or a bridginggroup.

“Cycloalkylalkyl” means a cycloalkyl-alkyl- group in which thecycloalkyl and alkyl moieties are as defined herein. Exemplarymonocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl,cyclohexylmethyl and cycloheptylmethyl. The group may be a terminalgroup or a bridging group. If the group is a terminal group it is bondedto the remainder of the molecule through the alkyl group.

“Cycloalkylalkenyl” means a cycloalkyl-alkenyl- group in which thecycloalkyl and alkenyl moieties are as defined herein. The group may bea terminal group or a bridging group. If the group is a terminal groupit is bonded to the remainder of the molecule through the alkenyl group.

“Cycloalkylheteroalkyl” means a cycloalkyl-heteroalkyl- group in whichthe cycloalkyl and heteroalkyl moieties are as defined herein. The groupmay be a terminal group or a bridging group. If the group is a terminalgroup it is bonded to the remainder of the molecule through theheteroalkyl group.

“Cycloalkyloxy” refers to a cycloalkyl-O— group in which cycloalkyl isas defined herein. Preferably the cycloalkyloxy is a C₁-C₆cycloalkyloxy.Examples include, but are not limited to, cyclopropanoxy andcyclobutanoxy. The group may be a terminal group or a bridging group. Ifthe group is a terminal group it is bonded to the remainder of themolecule through the oxygen atom.

“Cycloalkenyloxy” refers to a cycloalkenyl-O— group in which thecycloalkenyl is as defined herein. Preferably the cycloalkenyloxy is aC₁-C₆cycloalkenyloxy. The group may be a terminal group or a bridginggroup. If the group is a terminal group it is bonded to the remainder ofthe molecule through the oxygen atom.

Failure of treatment can be defined as condition in which a non-fastingblood glucose level of less than 200 mg/di and a blood glucose levelduring fasting (deprived of food for at least 8 hr) of less than 126mg/dl are retained after administration of the agent in its recommendeddose.

“Haloalkyl” refers to an alkyl group as defined herein in which one ormore of the hydrogen atoms has been replaced with a halogen atomselected from the group consisting of fluorine, chlorine, bromine andiodine. A haloalkyl group typically has the formulaC_(n)H_((2n+1−m))X_(m) wherein each X is independently selected from thegroup consisting of F, Cl, Br and I. In groups of this type n istypically from 1 to 10, more preferably from 1 to 6, most preferably 1to 3. m is typically 1 to 6, more preferably 1 to 3. Examples ofhaloalkyl include fluoromethyl, difluoromethyl and trifluoromethyl.

“Haloalkenyl” refers to an alkenyl group as defined herein in which oneor more of the hydrogen atoms has been replaced with a halogen atomindependently selected from the group consisting of F, Cl, Br and I.

“Haloalkynyl” refers to an alkynyl group as defined herein in which oneor more of the hydrogen atoms has been replaced with a halogen atomindependently selected from the group consisting of F, Cl, Br and I.

“Halogen” represents chlorine, fluorine, bromine or iodine.

“Heteroalkyl” refers to a straight- or branched-chain alkyl grouppreferably having from 2 to 12 carbons, more preferably 2 to 6 carbonsin the chain, in which one or more of the carbon atoms (and anyassociated hydrogen atoms) are each independently replaced by aheteroatomic group selected from S, O, P and NR′ where R′ is selectedfrom the group consisting of H, optionally substituted C₁-C₁₂alkyl,optionally substituted C₃-C₁₂cycloalkyl, optionally substitutedC₆-C₁₈aryl, and optionally substituted C₁-C₁₈heteroaryl. Exemplaryheteroalkyls include alkyl ethers, secondary and tertiary alkyl amines,amides, alkyl sulfides, and the like. Examples of heteroalkyl alsoinclude hydroxyC₁-C₆alkyl, C₁-C₆alkyloxyC₁-C₆alkyl, aminoC₁-C₆alkyl,C₁-C₆alkylaminoC₁-C₆alkyl, and di(C₁-C₆alkyl)aminoC₁-C₆alkyl. The groupmay be a terminal group or a bridging group.

“Heteroalkyloxy” refers to a heteroalkyl-O— group in which heteroalkylis as defined herein. Preferably the heteroalkyloxy is aC₂-C₆heteroalkyloxy. The group may be a terminal group or a bridginggroup.

“Heteroaryl” either alone or part of a group refers to groups containingan aromatic ring (preferably a 5 or 6 membered aromatic ring) having oneor more heteroatoms as ring atoms in the aromatic ring with theremainder of the ring atoms being carbon atoms. Suitable heteroatomsinclude nitrogen, oxygen and sulphur. Examples of heteroaryl includethiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole,benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan,isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole,pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole,isoindole, 1H-indazole, purine, quinoline, isoquinoline, phthalazine,naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine,acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole,isooxazole, furazane, phenoxazine, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5-,or 8-quinolyl, 1-, 3-, 4-, or 5-isoquinolinyl 1-, 2-, or 3-indolyl, and2-, or 3-thienyl. A heteroaryl group is typically a C₁-C₁₈ heteroarylgroup. The group may be a terminal group or a bridging group.

“Heteroarylalkyl” means a heteroaryl-alkyl group in which the heteroaryland alkyl moieties are as defined herein. Preferred heteroarylalkylgroups contain a lower alkyl moiety. Exemplary heteroarylalkyl groupsinclude pyridylmethyl. The group may be a terminal group or a bridginggroup. If the group is a terminal group it is bonded to the remainder ofthe molecule through the alkyl group.

“Heteroarylalkenyl” means a heteroaryl-alkenyl- group in which theheteroaryl and alkenyl moieties are as defined herein. The group may bea terminal group or a bridging group. If the group is a terminal groupit is bonded to the remainder of the molecule through the alkenyl group.

“Heteroarylheteroalkyl” means a heteroaryl-heteroalkyl- group in whichthe heteroaryl and heteroalkyl moieties are as defined herein. The groupmay be a terminal group or a bridging group. If the group is a terminalgroup it is bonded to the remainder of the molecule through theheteroalkyl group.

“Heteroaryloxy” refers to a heteroaryl-O— group in which the heteroarylis as defined herein. Preferably the heteroaryloxy is aC₁-C₁₈heteroaryloxy. The group may be a terminal group or a bridginggroup. If the group is a terminal group it is bonded to the remainder ofthe molecule through the oxygen atom.

“Heterocyclic” refers to saturated, partially unsaturated or fullyunsaturated monocyclic, bicyclic or polycyclic ring system containing atleast one heteroatom selected from the group consisting of nitrogen,sulfur and oxygen as a ring atom. Examples of heterocyclic moietiesinclude heterocycloalkyl, heterocycloalkenyl and heteroaryl.

“Heterocycloalkenyl” refers to a heterocycloalkyl group as definedherein but containing at least one double bond. A heterocycloalkenylgroup typically is a C₂-C₁₂ heterocycloalkenyl group. The group may be aterminal group or a bridging group.

“Heterocycloalkyl” refers to a saturated monocyclic, bicyclic, orpolycyclic ring containing at least one heteroatom selected fromnitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at leastone ring. Each ring is preferably from 3 to 10 membered, more preferably4 to 7 membered. Examples of suitable heterocycloalkyl substituentsinclude pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl,piperazyl, tetrahydropyranyl, morphilino, 1,3-diazapane, 1,4-diazapane,1,4-oxazepane, and 1,4-oxathiapane. A heterocycloalkyl group typicallyis a C₂-C₁₂heterocycloalkyl group. The group may be a terminal group ora bridging group.

“Heterocycloalkylalkyl” refers to a heterocycloalkyl-alkyl- group inwhich the heterocycloalkyl and alkyl moieties are as defined herein.Exemplary heterocycloalkylalkyl groups include(2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl) methyl. The groupmay be a terminal group or a bridging group. If the group is a terminalgroup it is bonded to the remainder of the molecule through the alkylgroup.

“Heterocycloalkylalkenyl” refers to a heterocycloalkyl-alkenyl- group inwhich the heterocycloalkyl and alkenyl moieties are as defined herein.The group may be a terminal group or a bridging group. If the group is aterminal group it is bonded to the remainder of the molecule through thealkenyl group.

“Heterocycloalkylheteroalkyl” means a heterocycloalkyl-heteroalkyl-group in which the heterocycloalkyl and heteroalkyl moieties are asdefined herein. The group may be a terminal group or a bridging group.If the group is a terminal group it is bonded to the remainder of themolecule through the heteroalkyl group.

“Heterocycloalkyloxy” refers to a heterocycloalkyl-O— group in which theheterocycloalkyl is as defined herein. Preferably theheterocycloalkyloxy is a C₁-C₆heterocycloalkyloxy. The group may be aterminal group or a bridging group. If the group is a terminal group itis bonded to the remainder of the molecule through the oxygen atom.

“Heterocycloalkenyloxy” refers to a heterocycloalkenyl-O— group in whichheterocycloalkenyl is as defined herein. Preferably theHeterocycloalkenyloxy is a C₁-C₆ Heterocycloalkenyloxy. The group may bea terminal group or a bridging group. If the group is a terminal groupit is bonded to the remainder of the molecule through the oxygen atom.

“Hydroxyalkyl” refers to an alkyl group as defined herein in which oneor more of the hydrogen atoms has been replaced with an OH group. Ahydroxyalkyl group typically has the formula C_(n)H_((2n+1−x))(OH)_(x).In groups of this type n is typically from 1 to 10, more preferably from1 to 6, most preferably 1 to 3. x is typically 1 to 6, more preferably 1to 3.

“Sulfinyl” means an R—S(═O)— group in which the R group may be OH,alkyl, cycloalkyl, heterocycloalkyl; aryl or heteroaryl group as definedherein. The group may be a terminal group or a bridging group. If thegroup is a terminal group it is bonded to the remainder of the moleculethrough the sulfur atom.

“Sulfinylamino” means an R—S(═O)—NH— group in which the R group may beOH, alkyl, cycloalkyl, heterocycloalkyl; aryl or heteroaryl group asdefined herein. The group may be a terminal group or a bridging group.If the group is a terminal group it is bonded to the remainder of themolecule through the nitrogen atom.

“Sulfonyl” means an R—S(═O)₂— group in which the R group may be OH,alkyl, cycloalkyl, heterocycloalkyl; aryl or heteroaryl group as definedherein. The group may be a terminal group or a bridging group. If thegroup is a terminal group it is bonded to the remainder of the moleculethrough the sulfur atom.

“Sulfonylamino” means an R—S(═O)₂—NH— group. The group may be a terminalgroup or a bridging group. If the group is a terminal group it is bondedto the remainder of the molecule through the nitrogen atom.

It is understood that included in the family of compounds of Formula (I)are isomeric forms including diastereoisomers, enantiomers, tautomers,and geometrical isomers in “E” or “Z” configurational isomer or amixture of E and Z isomers. It is also understood that some isomericforms such as diastereomers, enantiomers, and geometrical isomers can beseparated by physical and/or chemical methods and by those skilled inthe art. For those compounds where there is the possibility of geometricisomerism the applicant has drawn the isomer that the compound isthought to be although it will be appreciated that the other isomer maybe the correct structural assignment.

Some of the compounds of the disclosed embodiments may exist as singlestereoisomers, racemates, and/or mixtures of enantiomers and fordiastereomers. All such single stereoisomers, racemates and mixturesthereof, are intended to be within the scope of the subject matterdescribed and claimed.

Additionally, Formula (I) is intended to cover, where applicable,solvated as well as unsolvated forms of the compounds. Thus, eachformula includes compounds having the indicated structure, including thehydrated as well as the non-hydrated forms.

The term “pharmaceutically acceptable salts” refers to salts that retainthe desired biological activity of the above-identified compounds, andinclude pharmaceutically acceptable acid addition salts and baseaddition salts. Suitable pharmaceutically acceptable acid addition saltsof compounds of Formula (I) may be prepared from an inorganic acid orfrom an organic acid. Examples of such inorganic acids are hydrochloric,sulfuric, and phosphoric acid. Appropriate organic acids may be selectedfrom aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic andsulfonic classes of organic acids, examples of which are formic, acetic,propanoic, succinic, glycolic, gluconic, lactic, malic, tartaric,citric, fumaric, maleic, alkyl sulfonic, arylsulfonic. Additionalinformation on pharmaceutically acceptable salts can be found inRemington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co.,Easton, Pa. 1995. In the case of agents that are solids, it isunderstood by those skilled in the art that the inventive compounds,agents and salts may exist in different crystalline or polymorphicforms, all of which are intended to be within the scope of the presentinvention and specified formulae.

“Prodrug” means a compound that undergoes conversion to a compound offormula (I) within a biological system, usually by metabolic means (e.g.by hydrolysis, reduction or oxidation). For example an ester prodrug ofa compound of formula (I) containing a hydroxyl group may be convertibleby hydrolysis in vivo to the parent molecule. Suitable esters ofcompounds of formula (I) containing a hydroxyl group, are for exampleacetates, citrates, lactates, tartrates, malonates, oxalates,salicylates, propionates, succinates, fumarates, maleates,methylene-bis-p-hydroxynaphthoates, gestisates, isethionates,di-p-toluoyltartrates, methanesulphonates, ethanesulphonates,benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates andquinates. As another example an ester prodrug of a compound of formula(I) containing a carboxy group may be convertible by hydrolysis in vivoto the parent molecule. (Examples of ester prodrugs are those describedby F. J. Leinweber, Drug Metab. Res., 18:379, 1987). Similarly, an acylprodrug of a compound of formula (I) containing an amino group may beconvertible by hydrolysis in vivo to the parent molecule (Many examplesof prodrugs for these and other functional groups, including amines, aredescribed in Prodrugs: Challenges and Rewards (Parts 1 and 2); Ed V.Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag and J Tilley;Springer, 2007).

The term “therapeutically effective amount” or “effective amount” is anamount sufficient to effect beneficial or desired clinical results. Aneffective amount can be administered in one or more administrations. Aneffective amount is typically sufficient to palliate, ameliorate,stabilize, reverse, slow or delay the progression of the disease state.

Specific compounds of the invention include the following:

or pharmaceutically acceptable salt or prodrug thereof.

The compounds have the ability to inhibit 11β-HSD1. The ability toinhibit 11β-HSD1 may be a result of the compounds acting directly andsolely on the 11β-HSD1 to modulate/potentiate biological activity.However, it is understood that the compounds may also act at leastpartially on other factors associated with 11β-HSD1 activity.

The inhibition of 11β-HSD1 may be carried out in any of a number of waysknown in the art. For example if inhibition of 11β-HSD1 in vitro isdesired an appropriate amount of the compound may be added to a solutioncontaining the 11β-HSD1. In circumstances where it is desired to inhibit11β-HSD1 in a mammal, the inhibition of the 11β-HSD1 typically involvesadministering the compound to a mammal containing the 11β-HSD1.

Accordingly the compounds may find a multiple number of applications inwhich their ability to inhibit 11β-HSD1 enzyme of the type mentionedabove can be utilised.

Accordingly compounds of the invention would be expected to have usefultherapeutic properties especially in relation to diabetes,hyperglycemia, low glucose tolerance, hyperinsulinemia, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, dyslipidemia, obesity,abdominal obesity, glaucoma, hypertension, atherosclerosis and itssequelae, retinopathy and other ocular disorders, nephropathy,neuropathy, myopathy, osteoporosis, osteoarthritis, dementia,depression, neurodegenerative disease, psychiatric disorders, Polycysticovaries syndrome, infertility, Cushing's Disease, Cushing's syndrome,virus diseases, and inflammatory diseases.

Administration of compounds within Formula (I) to humans can be by anyof the accepted modes for enteral administration such as oral or rectal,or by parenteral administration such as subcutaneous, intramuscular,intravenous and intradermal routes. Injection can be bolus or viaconstant or intermittent infusion. The active compound is typicallyincluded in a pharmaceutically acceptable carrier or diluent and in anamount sufficient to deliver to the patient a therapeutically effectivedose. In various embodiments the activator compound may be selectivelytoxic or more toxic to rapidly proliferating cells, e.g. canceroustumours, than to normal cells.

In using the compounds of the invention they can be administered in anyform or mode which makes the compound bioavailable. One skilled in theart of preparing formulations can readily select the proper form andmode of administration depending upon the particular characteristics ofthe compound selected, the condition to be treated, the stage of thecondition to be treated and other relevant circumstances. We refer thereader to Remingtons Pharmaceutical Sciences, 19^(th) edition, MackPublishing Co. (1995) for further information.

The compounds of the present invention can be administered alone or inthe form of a pharmaceutical composition in combination with apharmaceutically acceptable carrier, diluent or excipient. The compoundsof the invention, while effective themselves, are typically formulatedand administered in the form of their pharmaceutically acceptable saltsas these forms are typically more stable, more easily crystallised andhave increased solubility.

The compounds are, however, typically used in the form of pharmaceuticalcompositions which are formulated depending on the desired mode ofadministration. As such in some embodiments the present inventionprovides a pharmaceutical composition including a compound of Formula(I) and a pharmaceutically acceptable carrier, diluent or excipient. Thecompositions are prepared in manners well known in the art.

The invention in other embodiments provides a pharmaceutical pack or kitcomprising one or more containers filled with one or more of theingredients of the pharmaceutical compositions of the invention. In sucha pack or kit can be found a container having a unit dosage of theagent(s). The kits can include a composition comprising an effectiveagent either as concentrates (including lyophilized compositions), whichcan be diluted further prior to use or they can be provided at theconcentration of use, where the vials may include one or more dosages.Conveniently, in the kits, single dosages can be provided in sterilevials so that the physician can employ the vials directly, where thevials will have the desired amount and concentration of agent(s).Associated with such container(s) can be various written materials suchas instructions for use, or a notice in the form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals or biological products, which notice reflects approvalby the agency of manufacture, use or sale for human administration.

The compounds of the invention may be used or administered incombination with one or more additional drug(s) for the treatment of thedisorder/diseases mentioned. The components can be administered in thesame formulation or in separate formulations. If administered inseparate formulations the compounds of the invention may be administeredsequentially or simultaneously with the other drug(s).

In addition to being able to be administered in combination with one ormore additional drugs, the compounds of the invention may be used in acombination therapy. When this is done the compounds are typicallyadministered in combination with each other. Thus one or more of thecompounds of the invention may be administered either simultaneously (asa combined preparation) or sequentially in order to achieve a desiredeffect. This is especially desirable where the therapeutic profile ofeach compound is different such that the combined effect of the twodrugs provides an improved therapeutic result.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol, and the like), and suitable mixtures thereof, vegetable oils(such as olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservative,wetting agents, emulsifying agents, and dispersing agents. Prevention ofthe action of micro-organisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents such as sugars, sodium chloride,and the like. Prolonged absorption of the injectable pharmaceutical formmay be brought about by the inclusion of agents that delay absorptionsuch as aluminium monostearate and gelatin.

If desired, and for more effective distribution, the compounds can beincorporated into slow release or targeted delivery systems such aspolymer matrices, liposomes, and microspheres.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions that can bedissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in microencapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminiummetahydroxide, bentonite, agar-agar, and tragacanth, and mixturesthereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Dosage forms for topical administration of a compound of this inventioninclude powders, patches, sprays, ointments and inhalants. The activecompound is mixed under sterile conditions with a pharmaceuticallyacceptable carrier and any needed preservatives, buffers, or propellantswhich may be required.

The amount of compound administered will preferably treat and reduce oralleviate the condition. A therapeutically effective amount can bereadily determined by an attending diagnostician by the use ofconventional techniques and by observing results obtained underanalogous circumstances. In determining the therapeutically effectiveamount a number of factors are to be considered including but notlimited to, the species of animal, its size, age and general health, thespecific condition involved, the severity of the condition, the responseof the patient to treatment, the particular compound administered, themode of administration, the bioavailability of the preparationadministered, the dose regime selected, the use of other medications andother relevant circumstances.

A preferred dosage will be a range from about 0.01 to 300 mg perkilogram of body weight per day. A more preferred dosage will be in therange from 0.1 to 100 mg per kilogram of body weight per day, morepreferably from 0.2 to 80 mg per kilogram of body weight per day, evenmore preferably 0.2 to 50 mg per kilogram of body weight per day. Asuitable dose can be administered in multiple sub-doses per day.

The compound of the invention may also be administered in combinationwith (or simultaneously or sequentially with) an adjuvant to increasecompound performance. Suitable adjuvants may include (a) dipeptidylpeptidase-IV (DP-IV) inhibitors; (b) insulin sensitizing agents; (iv)biguanides; (c) insulin and insulin mimetics; (d) sulfonylureas andother insulin secretagogues; (e) alpha-glucosidase inhibitors; and (f)GLP-1, GLP-1 analogs, and GLP-1 receptor agonists. The adjuvants may bepart of the same composition, or the adjuvants may be administeredseparately (either simultaneously or sequentially). The order of theadministration of the composition and the adjuvant will generally beknown to the medical practitioner involved and may be varied.

Synthesis of Compounds of the Invention

The agents of the various embodiments may be prepared using the reactionroutes and synthesis schemes as described below, employing thetechniques available in the art using starting materials that arereadily available. The preparation of particular compounds of theembodiments is described in detail in the following examples, but theartisan will recognize that the chemical reactions described may bereadily adapted to prepare a number of other agents of the variousembodiments. For example, the synthesis of non-exemplified compounds maybe successfully performed by modifications apparent to those skilled inthe art, e.g. by appropriately protecting interfering groups, bychanging to other suitable reagents known in the art, or by makingroutine modifications of reaction conditions. A list of suitableprotecting groups in organic synthesis can be found in T. W. Greene'sProtective Groups in Organic Synthesis, 3^(rd) Edition, John Wiley &Sons, 1991. Alternatively, other reactions disclosed herein or known inthe art will be recognized as having applicability for preparing othercompounds of the various embodiments.

Reagents useful for synthesizing compounds may be obtained or preparedaccording to techniques known in the art.

The symbols, abbreviations and conventions in the processes, schemes,and examples are consistent with those used in the contemporaryscientific literature. Specifically but not meant as limiting, thefollowing abbreviations may be used in the examples and throughout thespecification.

g (grams)

L (liters)

Hz (Hertz)

mol (moles)

RT (room temperature)

min (minutes)

MeOH (methanol)

CHCl₃ (chloroform)

DCM (dichloromethane)

DMSO (dimethylsulfoxide)

EtOAc (ethyl acetate)

mg (milligrams)

mL (milliliters)

psi (pounds per square inch)

mM (millimolar)

MHz (megahertz)

h (hours)

TLC (thin layer chromatography)

EtOH (ethanol)

CDCl₃ (deuterated chloroform)

HCl (hydrochloric acid)

DMF (N, N-dimethylformamide)

THF (tetrahydrofuran)

K₂CO₃ (potassium carbonate)

Na₂SO₄ (sodium sulfate)

RM (Reaction Mixture)

Unless otherwise indicated, all temperatures are expressed in ° C.(degree centigrade). All reactions conducted at room temperature unlessotherwise mentioned.

All the solvents and reagents used are commercially available andpurchased from Sigma Aldrich, Fluka, Acros, Spectrochem, Alfa Aesar,Avra, Qualigens, Merck, Rankem and Leonid Chemicals.

¹H NMR spectra were recorded on a Bruker A V 300. Chemical shifts areexpressed in parts per million (ppm, δ units). Coupling constants are inunits of hertz (Hz). Splitting patterns describe apparent multiplicitiesand are designated as s (singlet), d (doublet), t (triplet), q(quartet), m (multiplet), or br (broad).

Mass spectra were obtained on single quadruple 6120 LCMS from Agilenttechnologies, using either atmospheric chemical ionization (APCI) orElectrospray ionization (ESI) or in the combination of these twosources.

All samples were run on SHIMADZU system with an LC-20 AD pump, SPD-M20Adiode array detector, SIL-20A auto sampler.

Synthetic Scheme 1

One scheme for making certain compounds of the invention is shown inscheme 1 below.

Synthesis of5-[1-(1H-indol-3-yl)ethyl]-2,2-dimethyl-1,3-dioxane-4,6-dione(Intermediate-1)

A 100 mL RB flask fitted with magnetic stirrer was charged with StartingMaterial 1 (4.0 g, 34 mmol), Starting Material 2 (4.92, 34 mmol) andStarting Material 3 (3 g, 68 mmol) in 75 mL of acetonitrile. Theresulting solution was stirred at room temperature overnight. Aftercompletion of the reaction (reaction monitored by TLC), the Solvent wasremoved under reduced pressure, and the resulting crude compound waspurified by column chromatography on silica gel (230-400 mesh) usingPetroleum ether (60-80) and ethyl acetate as eluent. The product(intermediate 1) was obtained as a brown liquid (2.51 g). LC-MS(M−H)⁺=286.

Synthesis of ethyl 3-(1H-indol-3-yl)butanoate (Intermediate-2)

A 100 mL RB flask fitted with magnetic stirrer was charged withintermediate-1 (2.5 g, 8.7 mmol) in 50 mL of pyridine and 8 ml ofethanol. To this mixture copper powder (0.4 g, 5 mol %) was added. Thenthe resulting reaction mass was refluxed at 110° C. for 3 hours. Aftercompletion of the reaction (reaction monitored by TLC), solvent wasremoved from the reaction mass and the reaction mass was diluted with100 mL of ethyl acetate, washed with 50 mL 1.5N HCl (2×25 mL) and brinesolution. Then the organic layer was dried over anhydrous MgSO₄. Thesolvent was removed under reduced pressure, and the resulting crudecompound was purified by column chromatography on silica gel (230-400mesh) using Petroleum ether (60-80) and ethyl acetate as eluent. Theproduct (intermediate 2) was obtained as a brown liquid. (0.380 g).LC-MS (M+H)⁺==232.

Synthesis of ethyl 3-(1H-indol-3-yl)butanoic acid (Intermediate-3)

A 50 mL RB flask fitted with magnetic stirrer was charged with 6 mL ofmethanol and 2 mL of water. To the stirred solvent intermediate-2 (0.145g, 0.62 mmol) and KOH (0.098 g, 2.54 mmol) was added. Then the resultingreaction mass was refluxed at 70° C. for 3 hours. After completion ofthe reaction (reaction monitored by TLC), solvent was removed from thereaction mass and the reaction mass was diluted with 20 mL of water. Theresulting aqueous layer was then washed with 20 mL of diethylether. Theaqueous layer was acidified by 1 NHCl to pH 5.5 and product wasextracted with ethyl acetate and the solvent was removed under reducedpressure. The product (intermediate 3) was obtained as a brown liquid(0.115 g). The product obtained above was directly taken for next stepwithout any purification.

Example 1 Compound (1):3-(1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)butan-1-one

Synthesis of Compound (1)

A 100 mL RB flask fitted with magnetic stirrer was charged withintermediate-3 (0.115 g, 0.56 mmol), Starting Material 4 (0.078 g, 0.56mmol), EDCI (0.162 g, 0.84 mmol), HOBt (0.104 g, 0.69 mmol) in 8 mL ofdichloromethane and it was cooled to 0° C. Then to the stirred solutiontriethylamine (0.301 mL, 2.0 mmol) was added. The resulting solution wasstirred at room temperature overnight. After completion of the reaction(reaction monitored by TLC), the reaction mass was diluted with 20 mL ofwater and organic layer was separated. The Solvent was removed underreduced pressure, and the resulting crude compound was purified by60-120 silical-gel chromatography by using petether ethylacetate aseluent. The final product obtained was pale yellow gummy solid (0.110g). ¹H NMR (300 MHz, CDCl3): δ 7.89 (s, 1H), 7.59-7.61 (m, 1H),7.27-7.30 (d, 1H), 7.00-7.13 (m, 2H), 6.94-6.95 (d, 1H), 4.41-4.60 (m,1H), 3.49-3.61 (m, 2H), 2.46-2.91 (m, 3H), 0.98-1.71 (m, 16H). LC-MS(M+H)⁺=325.2; HPLC purity: 92.84%.

Example 2 Compound (2):2-methyl-2-(1-methyl-1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one

Synthesis of methyl 1H-indol-3-ylacetate (Intermediate-4)

A 100 mL RB flask fitted with magnetic stirrer was charged with 15 mL ofMethanol. To the stirred solvent Starting Material-5 (2.0 g, 11.41 mmol)was added. The resulting mixture was cooled to zero degrees to whichconcentrated H₂SO₄ (0.5 mL) was added. The mixture was then stirred atambient temperatures for 1 hour. After completion of the reaction(reaction monitored by TLC), the solvent from the reaction mass wasremoved under reduced pressure. The resulting crude mass was taken inEthyl acetate (100 mL) and was washed with water (50 mL), Sodiumbicarbonate solution (100 mL×2) saturated brine solution (50 mL) and theorganic layer dried over anhydrous sodium sulphate. Then the solvent Wasremoved under reduced pressure. The product was obtained as brown syrup.(2.1 g). LC-MS (M+H)⁺=190.2.

Synthesis of methyl 2-methyl-2-(1-methyl-1H-indol-3-yl)propanoate(Intermediate-5)

A 100 mL 3 neck RB flask fitted with magnetic stirrer was charged with10 mL of dry THF. To the stirred solvent, diisopropyl amine (401.12 mg,3.964 mmol) was added and the resulting solution was cooled to −78degrees. Further n-BuLi (2.5 mL, 3.964 mmol) was added to it and stirredfor 1 hour at 0° C. Once again the resulting solution was cooled to −78degrees to which Intermediate-4 (150 mg, 0.7928 mmol) was added andstirred for 1 hour. Then Methyl Iodide was added and the resulting masswas stirred at ambient temperature for 15 hours. After completion of thereaction (reaction monitored by TLC), the reaction mass was quenchedwith saturated ammonium chloride and was extracted using EtOAc (100mL×3). The combined organic layer washed with brine was dried and thesolvent was removed under reduced pressure. The resulting crude compoundwas purified by column chromatography on silica gel (120 meshes) usingPetroleum ether (60-80) and ethyl acetate as eluent. The product wasobtained as brown syrup. (150 mg). LC-MS (M+H)⁺=232.2.

Synthesis of 2-methyl-2-(1-methyl-1H-indol-3-yl)propanoic acid(Intermediate-6)

A 100 mL RB flask fitted with magnetic stirrer was charged with THF 5mL. To the stirred solvent Intermediate-5 (150 mg, 0.6485 mmol) wasadded which was followed by the addition of NaOH (77.82 mg; 1.945 mmol),and water-methanol mixture (1 mL, 1:1). The resulting mass was heated at70° C. for 4 hours. After completion of the reaction, the solvent fromthe reaction mass was removed under reduced pressure. The crude mass wastreated with water and washed with ether (50 mL×3). The resultingaqueous solution was acidified to pH=1 to 2 by using 1N HCl andextracted with DCM (50 mL×3). The combined DCM layers were washed withbrine, dried over anhydrous Na₂SO₄ and the solvent was removed underreduced pressure to give Intermediate-6 as brown solid (85 mg). LC-MS(M+H)⁺=218.2.

Synthesis of Compound (2)

Compound (2) was synthesized by following the procedure used to makecompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified using silicagel column where Petroleum ether: Ethyl acetate was used as an eluent toobtain Compound (2). ¹H NMR (300 MHz, CDCl3): δ 7.43-7.48 (m, 1H),7.18-7.21 (d, 1H), 7.09-7.14 (t, 1H), 6.92-6.97 (t, 1H), 6.75-6.80 (d,1H), 4.50-4.75 (m, 1H), 3.57-3.98 (m, 4H), 2.28-2.45 (m, 1H), 1.47-1.58(m, 8H), 1.37-1.40 (m, 6H), 0.94-1.09 (m, 5H). LC-MS (M+H)⁺=339.2; HPLCpurity: 98.09%.

Example 33-(5-methyl-1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one(3)

Synthesis of ethyl (2E)-3-(5-methyl-1H-indol-3-yl)prop-2-enoate(Intermediate-7)

Triethylphosphenoacetate (9.4 mmol) was taken in THF (20 mL) to whichNaH (60%) was added portion wise at −5° C. The reaction mass thusobtained was maintained at same temperature for 45 min. To this theStarting Material-6 (750 mg, 4.7 mmol) was added and the resultingreaction mass was stirred at RT for 24 hours. Then reaction mass wasdiluted with ethyl acetate and the organic layer was separated and theseparated organic layer was washed with saturated NaHCO₃, dried overanhydrous Na₂SO₄ and concentrated. The crude product thus obtained waspurified by 60-120 silica gel by using hexanes: EtOAc as eluent to giveIntermediate 7 (490 mg). LC-MS (M+H)⁺=230.

Synthesis of ethyl 3-(5-methyl-1H-indol-3-yl)propanoate (Intermediate-8)

Intermediate-7 (1.31 g, 5.6 mmol) was taken in MeOH (25 mL) to which 10%Pd/C (150 mg) was added. The resulting reaction mass was stirred underH₂ atmosphere (25 psi) for 10 hours. Further the reaction mass thusobtained was filtered through celite bed and concentrated to giveIntermediate-8 (820 mg). LC-MS (M+H)⁺=232.

Synthesis of 3-(5-methyl-1H-indol-3-yl)propanoic acid (Intermediate-9)

Intermediate −8 (600 mg, 2.5 mmol) was taken in MeOH (8 mL) to which KOH(500 mg, 9.0 mmol) and 1 mL of water was added. Resulting reactionmixture was refluxed for 3 hours. The reaction mixture was concentratedand then diluted with water. The resulting mixture was acidified (pH=1to 2) with 1N HCl, extracted with EtOAc and then concentrated to giveIntermediate-9 (430 mg). LC-MS (M+H)⁺=204.

Synthesis of (3)

Compound (3) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(3). ¹H NMR (300 MHz, CDCl3): δ 7.90 (s, 1H), 7.31-7.34 (d, 1H),7.15-7.18 (m, 1H), 6.92-6.95 (m, 2H), 4.30-4.40 (m, 1H), 3.30-3.60 (m,1H), 2.45-3.06 (m, 5H), 2.38-2.39 (d, 3H), 1.18-1.77 (m, 13H). LC-MS(M+H)⁺=325.2; HPLC purity: 95.93%.

Example 43-(5-fluoro-1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one((4)

Synthesis of 3-(5-fluoro-1H-indol-3-yl)propanoic acid (Intermediate-10)

Intermediate-10 was synthesized by following the procedure used to makeIntermediate-9 (Scheme 4).

Synthesis of Compound (4)

Compound (4) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(4). ¹H NMR (300 MHz, CDCl3): δ 8.55 (s, 1H), 7.17-7.18 (d, 2H), 6.96(s, 1H), 6.80-6.85 (t, 1H), 4.43-4.57 (m, 1H), 3.41-3.58 (m, 1H),2.44-3.03 (m, 5H), 0.99-1.94 (m, 13H). LC-MS (M+H)⁺=329.1; HPLC purity:96.44%.

Example 52-(1H-indol-3-ylsulfanyl)-1-(octahydroquinolin-1(2H)-yl)ethanone (5)

Synthesis of 1H-indole-3-thiol (Intermediate-11)

A stirred solution of Starting Material-1 (2.93 g, 25.0 mmol) andthiourea (1.9 g, 25.0 mmol) in methanol (50 ml) was treated with amixture of iodine (6.35 g, 25.0 mmol) and KI (4.17 g, 25.0 mmol) inwater (25 ml), stirred for 1 hour, filtered through a cotton plug,concentrated in vacuo to remove methanol and ⅓ of water, and filteredconcentrated solution again. The tan solid filter cake is heated with 2MNaOH (50 ml) at 85° C. for 30 min, cooled and filtered. The filtrate isacidified with conc. HCl to pH=1 and filtered. This filter cake is driedunder a nitrogen stream to obtain the Intermediate-11 as cream-coloredsolid (900 mg).

Synthesis of methyl (1H-indol-3-ylsulfanyl)acetate (Intermediate-12)

Anhydrous potassium carbonate (2.1 g, 15.9 mmol) was added to a solutionof Intermediate-11 (0.8 g, 5.3 mmol) and ethyl 2-chlortoacetate (0.96ml, 5.3 mmol) in acetonitrile (30 mL). The resulting mixture was heatedto reflux under argon for 18 hours. The cooled mixture was filtered andconcentrated under vacuo. Water was added to the reaction mass andextracted with ethyl acetate. Combined organic extracts were dried over(MgSO₄) and concentrated to a crude gummy material, which was purifiedby column chromatography using hexane: ethyl acetate (1:9) to giveIntermediate-12 (300 mg).

Synthesis of (1H-indol-3-ylsulfanyl)acetic acid (Intermediate-13)

A mixture of (1H-Intermediate-12 (0.30 g, 1.27 mmol), 10% aqueous sodiumhydroxide solution (5 ml) and methanol (8 mL) were stirred at roomtemperature over-night. Reaction was monitored by TLC and LC-MS. Thenreaction mixture was concentrated under reduced pressure. Aqueous layerwas washed twice with DCM to remove organic impurities and was thenacidified with concentrated HCl. A white solid thus formed was isolatedby extraction and the solvent was removed under high vacuum. The crudereaction mass was purified by column chromatography usingethylacetate:hexane (1:1) as eluent to give Intermediate-13 (170 mg).

Synthesis of Compounds (5)

Compound (5) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(5). ¹H NMR (300 MHz, CDCl3): δ 8.78-8.96 (d, 1H), 7.73-7.76 (m, 1H),7.37 (s, 2H), 7.00-7.06 (m, 2H), 4.23-4.64 (m, 1H), 3.41-3.85 (m, 3H),2.26-3.41 (m, 3H), 1.25-1.72 (m, 11H). LC-MS (M+H)+=329.1; HPLC purity:98.84%.

Example 63-(5-chloro-1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one(6)

Synthesis of 3-(5-chloro-1H-indol-3-yl)propanoic acid (Intermediate-14)

Intermediate-14 was synthesized by following the procedure used to makeIntermediate-9 (Scheme 4).

Synthesis of Compound (6)

Compound (6) was synthesized by following the procedure used to makeCompound(1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(6). ¹H NMR (300 MHz, CDCl3): δ 8.05 (s, 1H), 7.48-7.51 (m, 1H),7.17-7.21 (m, 1H), 7.03-7.08 (m, 1H), 6.99 (s, 1H), 4.43-4.61 (m, 1H),3.45-3.59 (m, 1H), 2.96-3.04 (m, 2H), 2.45-2.93 (m, 3H), 1.21-1.66 (m,13H). LC-MS (M+H)⁺=345.2; HPLC purity: 89.78%.

Example 7 3-(5-methoxy-1 fi-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one (7)

Synthesis of 3-(5-methoxy-1H-indol-3-yl)propanoic acid (Intermediate-15)

Intermediate-15 was synthesized by following the procedure used to makeIntermediate-9 (Scheme 4).

Synthesis of Compound (7)

Compound (7) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(7). ¹H NMR (300 MHz, CDCl3): 8.19 (s, 1H), 7.22-7.25 (m, 1H), 7.04-7.05(d, 1H), 6.98 (s, 1H), 6.82-6.86 (m, 1H), 4.48-4.75 (m, 1H), 3.82 (s,3H), 3.48-3.72 (m, 1H), 3.04-3.13 (m, 2H), 2.74-2.95 (m, 1H), 2.56-2.72(m, 3H), 1.55-1.79 (m, 6H), 1.20-1.49 (m, 6H). LC-MS (M+H)⁺=341.2; HPLCpurity: 98.01%.

Example 8(2E)-3-(1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)prop-2-en-1-one (8)

Synthesis of ethyl (2E)-3-(1H-indol-3-yl)prop-2-enoate (Intermediate-16)

Intermediate-16 was synthesized by following the procedure used to makeIntermediate-7 (Scheme 4).

Synthesis of (2E)-3-(1H-indol-3-yl)prop-2-enoic acid (Intermediate-17)

Intermediate-17 was synthesized by following the procedure used to makeIntermediate-9 (Scheme 4).

Synthesis of Compound (8)

Compound (8) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(8). ¹H NMR (300 MHz, CDCl3): δ 8.50 (s, 1H), 7.80-7.88 (m, 3H),7.34-7.38 (m, 2H), 6.78-6.89 (m, 2H), 4.55-4.76 (m, 1H), 3.89-4.18 (m,1H), 3.05-3.48 (m, 1H), 2.06-2.71 (m, 1H), 1.29-1.81 (m, 12H). LC-MS(M+H)⁺=309.1; HPLC purity: 98.83%.

Example 9 2-(1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)ethanone (9)

Synthesis of Compound (9)

Compound (9) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(9). ¹H NMR (300 MHz, CDCl3): δ 8.20 (s, 1H), 7.61-7.63 (d, 1H),7.34-7.36 (d, 1H), 7.05-7.21 (m, 3H), 4.57-4.73 (m, 1H), 3.69-3.88 (m,3H), 3.10-3.50 (m, 1H), 2.60-3.00 (m, 1H), 1.01-1.90 (m, 12H). LC-MS(M+H)⁺=297.3; HPLC purity: 98.39%.

Example 102-(5-fluoro-1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)ethanone (10)

Synthesis of Compound (10)

Compound (10) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(10). ¹H NMR (300 MHz, CDCl3): δ 8.45 (s, 1H), 7.20-7.30 (m, 2H),7.00-7.15 (d, 1H), 6.95 (m, 1H), 4.53-4.73 (m, 1H), 3.64-3.91 (m, 2H),2.60-3.03 (m, 1H), 1.29-1.84 (m, 14H). LC-MS (M+H)⁺=315.1; HPLC purity:89.32%.

Example 11 4-(1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)butan-1-one(11)

Synthesis of Compound (11)

Compound (11) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(11). ¹H NMR (300 MHz, CDCl3): δ 8.04 (s, 1H), 7.59-7.62 (d, 1H),7.34-7.36 (d, 1H), 7.07-7.20 (m, 2H), 7.00 (s, 1H), 4.48-4.75 (m, 1H),3.48-3.62 (m, 1H), 2.88-3.15 (m, 1H), 2.80-2.85 (m, 2H), 2.31-2.52 (m,2H), 2.02-2.11 (m, 2H), 1.51-1.80 (m, 7H), 1.23-1.38 (m, 6H). LC-MS(M+H)⁺=325.2; HPLC purity: 91.10%.

Example 123-(1H-indol-3-yl)-1-(4-methyloctahydroquinolin-1(2H)-yl)propan-1-one(HS_A_287) (12)

Synthesis of 4-methyldecahydroquinoline (Intermediate-18)

To a solution of Starting Material-9 (1 g, 6.9 mmol) in 15 mL of aceticacid, PtO₂ (0.793 g, 3.5 mmol) was added under N₂ atmosphere. N₂ gas waspurged for 5 min and then was degassed (two times). This reactionmixture as then kept under hydrogen atmosphere at 60 psi for 12 hours.The mixture was filtered and basified with 10% NaOH solution, extractedwith EtOAc and concentrated to give Intermediate-18 (700 mg).

Synthesis of Compound (12)

Compound (12) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(12). ¹H NMR (300 MHz, CDCl3): δ 8.03 (s, 1H), 7.61-7.63 (d, 1H),7.34-7.37 (d, 1H), 7.09-7.21 (m, 2H), 7.04 (s, 1H), 4.00 (m. 1H),3.11-3.16 (t, 2H), 2.97 (m, 1H), 2.61-2.81 (m, 2H), 1.28-1.84 (m, 13H),1.11-1.13 (d, 3H). LC-MS (M+H)+=325.2; HPLC purity: 99.15%.

Example 133-(1-methyl-1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one(13)

Synthesis of (13)

18-crown-6 ether (30 mg) and potassium tertiary butyl oxide (108 mg, 0.9mmol) was taken in benzene at 4° C. To this mixture (96) (250 mg, 0.8mmol) was added. The reaction mass was then stirred at room temperaturefor 15 minutes and was further cooled to 0° C. To this, Methyl iodide(171 mg, 1.2 mmol) dissolved in benzene was added. This reaction mixturewas then stirred at room temperature for 15 hours. The mixture wasfiltered through celite and concentrated. Resulted crude material waspurified by using silica gel column chromatography eluting with hexanes:EtOAc to give (13) (156 mg). ¹H NMR (300 MHz, CDCl3): δ 7.48-7.52 (m,1H), 6.97-7.18 (m, 3H), 6.78 (s, 1H), 4.42-4.60 (m, 1H), 3.60 (s, 3H),3.37-3.54 (m, 1H), 2.99-3.05 (m, 2H), 2.49-2.74 (m, 3H), 0.99-1.52 (m,13H). LC-MS (M+H)⁺=325.2; HPLC purity: 98.37%.

Example 14 3-(1H-indol-2-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one(14)

Synthesis of 3-(1H-indol-2-yl)propanoic acid (Intermediate-19)

Intermediate-19 was synthesized by following the procedure used to makeIntermediate-9 (Scheme 4).

Synthesis of Compound (14)

Compound (14) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(14). ¹H NMR (300 MHz, CDCl3) δ 9.28 (s, 1H), 7.41-7.43 (d, 1H),7.21-7.24 (d, 1H), 6.92-7.03 (m, 2H), 6.11 (s, 1H), 4.50-4.63 (m, 1H),3.43-3.63 (m, 1H), 2.50-3.02 (m, 5H), 1.16-1.67 (m, 13H). LC-MS(M+H)⁺=311.2; HPLC purity: 99.23%.

Example 153-(5-hydroxy-1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one(15)

Synthesis of 3-(5-methoxy-1H-indol-3-yl)propanoic acid (Intermediate-20)

Intermediate-20 was synthesized by following the procedure used to makeIntermediate-9 (Scheme 4).

Synthesis of3-(5-methoxy-1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one(Intermediate-21)

Intermediate-21 was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtainIntermediate-21.

Synthesis of Compound (15)

A 100 mL RB flask fitted with magnetic stirrer was charged with 5 mL ofDCM. Intermediate-21 (80 mg, 0.23 mmol) was then added to the stirredsolvent. The resulting solution was cooled to −78° C. to which 1Msolution of BBr₃ (188.6 mg, 0.74 mmol) in DCM was added. The reactionmass was further stirred at room temperature for 20 hours. Aftercompletion of the reaction (reaction monitored by TLC), reaction masswas diluted with 10 mL of water and extracted with DCM (2×10 mL). TheDCM layer was dried over of anhydrous Na₂SO₄. Solvent was removed underreduced pressure. Crude material was purified by silica gel columnchromatography eluting with hexanes: EtOAc to give Compound (15) (55mg). ¹H NMR (300 MHz, CDCl3): δ 7.79 (s, 1H), 7.11-7.15 (m, 1H),6.93-6.97 (m, 2H), 6.68-6.73 (m, 1H), 5.21 (s, 1H), 4.44-4.62 (m, 1H),3.45-3.59 (m, 1H), 2.94-3.03 (m, 2H), 2.66-2.91 (m, 1H), 2.53-2.63 (m,2H), 1.63-1.76 (m, 6H), 1.25-1.35 (m, 7H). LC-MS (M+H)⁺=327.2; HPLCpurity: 87.98%.

Example 163-(5-fluoro-2-methyl-1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one(16)

Synthesis of 3-(5-fluoro-2-methyl-1H-Indol-3-yl)propanoic acid(Intermediate-22)

Intermediate-22 was synthesized by following the procedure used to makeIntermediate-9 (Scheme 4).

Synthesis of Compound (16)

Compound (16) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(16). ¹H NMR (300 MHz, CDCl3): δ 7.81 (s, 1H), 7.10-7.18 (m, 2H),6.81-6.88 (m, 1H), 4.49-4.68 (m, 1H), 3.47-3.53 (m, 1H), 2.94-3.11 (m,2H), 2.48-3.11 (m, 3H), 2.37 (s, 3H), 1.30-1.78 (m, 13H). LC-MS(M+H)⁺=343.2; HPLC purity: 90.88%.

Example 173-(2-methyl-1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one(17)

Synthesis of 3-(2-methyl-1H-indol-3-yl)propanoic acid (Intermediate-23)

Intermediate-23 was synthesized by following the procedure used to makeIntermediate-9 (Scheme 4).

Synthesis of Compound (17)

Compound (17) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(17). ¹H NMR (300 MHz, CDCl3): δ 7.89 (s, 1H), 7.40-7.44 (m, 1H),7.17-7.19 (t, 1H), 6.98-7.05 (m, 2H), 4.43-4.62 (m, 1H), 3.38-3.47 (m,1H), 2.94-3.04 (m, 2H), 2.68-2.86 (m, 1H), 2.51-2.66 (m, 2H), 2.29 (s,3H), 1.52-1.70 (m, 6H), 1.21-1.34 (m, 7H). LC-MS (M+H)⁺=325.2; HPLCpurity: 94.48%.

Example 18 3-(1H-indol-1-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one(18)

Synthesis of 3-(1H-indol-1-yl)propanoic acid (Intermediate-25)

A 100 ml RB flask fitted with magnetic stirrer was charged with 10 ml ofDMF. To the stirred solvent Starting Material-1 (1.0 g, 8.53 mmol)followed by Sodium hydride (400 mg, 10.24 mmol) were added. Theresulting solution was stirred at room temperature for 1 hour. To theabove solution methyl-3-bromo-propionate (2.13 g, 12.79 mmol) was addedand stirred at room temperature for 24 hours. After completion of thereaction (reaction monitored by TLC), reaction mass was diluted with 30mL of ice cold water and washed with ether. Aqueous portion wasacidified with 1N HCl (pH=2) and was then extracted with EtOAc andconcentrated to give Intermediate-24 (900 mg).

Synthesis of Compound (18)

Compound (18) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(18). ¹H NMR (300 MHz, CDCl3): δ 7.38-7.43 (t, 1H), 7.16-7.28 (m, 1H),7.01-7.10 (m, 1H), 6.84-6.90 (m, 2H), 6.43-6.52 (m, 1H), 4.40-4.77 (m,1H), 4.30-4.35 (t, 2H), 3.14-3.35 (m, 3H), 2.42-2.78 (m, 2H), 1.57-1.61(t, 4H), 1.28-1.49 (m, 3H), 1.06-1.16 (m, 5H). LC-MS (M+H)⁺=311.1; HPLCpurity: 98.08%.

Example 191-(5-chloro-1H-indol-3-yl)-3-(octahydroquinolin-1(2H)-yl)propane-1,3-dione(19)

Synthesis of ethyl 3-(5-chloro-1H-indol-3-yl)-3-oxopropanoate(Intermediate-25)

To a 50 mL two neck RB 10 mL of dichloromethane was added. To thissolvent, ethylmalonylchloride (1.0 mL, 8.24 mmol) was added and thereaction mixture thus obtained was cooled to 0° C. To the cooledreaction mixture, TiCl₄ (0.9 ml, 8.24 mmol) was slowly added and themixture was stirred at room temperature for 20 min. The reaction mixturewas once again cooled to 0° C. and to the cooled mixture StartingMaterial-11 (0.5 g, 3.29 mmol) dissolved in 2 mL of dichloroethane wasadded and stirred at room temperature for 3 hours. The reaction mass wasquenched with 1N HCl solution and extracted with ethyl acetate. Organiclayers were concentrated, purified by silica-gel column chromatographyeluting with hexanes: EtOAc to give Intermediate-25 (566 mg).

Synthesis of ethyl 3-(5-chloro-1H-indol-3-yl)-3-oxopropanoic acid(Intermediate-26)

Intermediate-26 was synthesized by following the procedure used to makeintermediate-3 (1) (Scheme 1).

Synthesis of Compound (19)

Compound (19) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate (1:4) as eluent to obtainCompound (19). ¹H NMR (300 MHz, CDCl3): δ 10.58 (s, 1H), 8.22 (s, 1H),7.96 (s, 1H), 7.10 (m, 2H), 4.00-4.58 (m, 1H), 3.31-3.84 (m, 3H),2.50-3.10 (m, 1H), 1.16-1.82 (m, 13H). LC-MS (M+H)⁺=359.1; HPLC purity:90.09%.

Example 203-(4-methyl-1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one(20)

Synthesis of 4-methyl-1H-indole (Intermediate-27)

A 100 mL RB flask fitted with magnetic stirrer and reflux condenser wascharged with 60 mL of DMF. To the stirred solvent Starting Material-12(5 g, 33 mmol) was added followed by addition of Dimethyl formamidedimethyl acetal (13.1 mL, 99.2 mmol). To this reaction mixturePyrrolidine (3.2 mL, 39.6 mmol) was added and it was heated at 120° C.under Nitrogen atmosphere for 21 hours. After completion of the reactionthe mixture was cooled to room temperature and solvent was removed underreduced pressure. The resulting crude mass was taken in ether (250 mL)and was washed with water (50 mL×3) and saturated brine solution (50 mL)and the organic layer was dried over anhydrous sodium sulphate andconcentrated. Resulted crude material was taken in Ethyl acetate (50mL). To this 10% Pd/C (1.0 g, 10% w/w) was added and hydrogenated in aparr shaker for 2 hours. After completion of the reaction (reactionmonitored by TLC), the mixture was filtered through celite bed. Filtratewas concentrated to give crude product, which was purified by columnchromatography on silica gel (120 meshe) using Petroleum ether (60-80)and ethyl acetate as eluent to give Intermediate-27 (1.2 g).

Synthesis of 3-(4-methyl-1H-Indo)-3-yl)propanoic acid (Intermediate-28)

A 100 mL RB flask fitted with magnetic stirrer was charged with 2.5 mLof acetic acid. To the stirred solvent acetic anhydride 2.0 mL was addedfollowed by addition of acrylic acid (1.8 mL, 27.4 mmol). To thisstirred mixture, Intermediate-27 (1.2 g, 9.15 mmol) was added and thereaction mixture was further stirred at room temperature for 1 week.After completion of the reaction (reaction was monitored by TLC),reaction mass was basified using 5N NaOH (5 mL) and washed with Ethylacetate (100 mL×2). The aqueous layer was acidified with ConcentratedHCl (3 ML) and was extracted using Ethyl acetate (100 mL×3). Thecombined ethyl acetate layer was washed with brine solution andconcentrated to give Intermediate-28 (350 mg).

Synthesis of Compound (20)

Compound (20) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(20). ¹H NMR (300 MHz, CDCl3): δ 8.23 (s, 1H), 7.08-7.11 (t, 1H),6.93-6.99 (m, 1H), 6.88-6.89 (d, 1H), 6.73-6.77 (t, 1H), 4.46-4.50 (m,1H), 3.53-3.60 (m, 1H), 3.46-3.51 (m, 2H), 2.71-2.92 (m, 1H), 2.45-2.87(m, 6H), 1.71-1.77 (m, 5H), 1.29-1.39 (m, 7H). LC-MS (M+H)⁺=325.2; HPLCpurity: 96.28%.

Example 213-(1H-indol-3-yl)-1-(octahydroisoquinolin-2(1H)-yl)propan-1-one (21)

Synthesis of Compound (21)

Compound (21) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(21). ¹H NMR (300 MHz, CDCl3): δ 8.59 (s, 1H), 7.49-7.52 (d, 1H),7.24-7.26 (d, 1H), 6.98-7.10 (m, 2H), 6.90 (s, 1H), 4.44-4.66 (m, 1H),3.40-3.70 (m, 1H), 3.01-3.06 (m, 2H), 1.99-2.81 (m, 4H), 0.44-1.63 (m,12H). LC-MS (M+H)⁺=311.0; HPLC purity: 96.03%.

Example 221-(octahydro-4H-1,4-benzoxazin-4-yl)-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)butan-1-one(22)

Synthesis of 3,4-dihydro-2H-1,4-benzoxazine (Intermediate-29)

A solution of Starting Material-13(5 g, 33.5 mmol) in tetrahydrofuran(50 mL) was slowly added to a suspension of lithium aluminum hydride(3.18 g, 83.8 mmol) under N₂ atmosphere at 0° C. The reaction mixturewas refluxed for 16 h. The reaction mixture was diluted with EtOAc,quenched with 15% aqueous sodium hydroxide solution at 0° C., andextracted with ether, and concentrated to give Intermediate-29 as brownliquid (4.3 g).

Synthesis of octahydro-2H-1,4-benzoxazine (Intermediate-30

To a solution of Intermediate-29 (1.5 g, 11.1 mmol) in 20 mL of aceticacid, 10% PtO₂ (252 mg) was added, and hydrogenated at 60 psi for 5 h.The mixture was filtered and basified with 10% NaOH solution, extractedwith diethyl ether, dried over sodium sulphate and concentrated to giveIntermediate-30 as brown liquid (520 mg).

Synthesis of 3-(1H-pyrrolo[2,3-b]pyridin-3-yl)butanoic acid(Intermediate-31)

Intermediate-31 was synthesized by following the procedure used to makeIntermediate-3 (Scheme 1).

Synthesis of Compound (22)

Compound (22) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(22). ¹H NMR (300 MHz, DMSO-d6): δ 11.31 (s, 1H), 8.15-8.17 (m, 1H),7.95-7.99 (m, 1H), 7.25-7.29 (d, 1H), 6.98-7.04 (m, 1H), 3.99-4.10 (m,1H), 3.43-3.74 (m, 4H), 2.63-3.10 (m, 3H), 1.15-1.99 (m, 12H). LC-MS(M+H)⁺=328.2; HPLC purity: 95.42%.

Example 23N-tert-butyl-2-[3-(1H-indol-3-yl)propanoyl]decahydroisoquinoline-3-carboxamide(23)

Synthesis of Compound (23)

Compound (23) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate (1:4) as eluent to obtainCompound (23). ¹H NMR (300 MHz, CDCl3): 7.99 (s, 1H), 7.48-7.55 (m, 1H),7.28-7.30 (d, 1H), 7.03-7.15 (m, 2H), 6.97 (s, 1H), 5.57-5.72 (d, 1H),4.95 (s, 1H), 3.24-4.33 (m, 3H), 3.05-3.37 (m, 1H), 2.09-2.86 (m, 3H),1.15-1.56 (m, 20H). LC-MS (M−H)⁺=408.2; HPLC purity: 98.47%.

Example 243-(5-hydroxy-1-methyl-1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one(24)

Synthesis of Compound (24)

Compound (24) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(24). ¹H NMR (300 MHz, CDCl3) δ 6.95-7.02 (m, 2H), 6.76-6.79 (d, 1H),6.70-6.79 (d, 1H), 4.44-4.62 (m, 1H), 3.56-3.57 (d, 3H), 3.41-3.50 (m,1H), 2.91-3.06 (m, 2H), 2.67-2.84 (m, 1H), 2.48-2.65 (m, 2H), 1.57-1.71(m, 4H), 1.46-1.47 (d, 2H), 1.18-1.34 (m, 7H). LC-MS (M+H)⁺=341.2; HPLCpurity: 97.31%.

Example 252-(1H-indol-3-yloxy)-1-(octahydroquinolin-1(2H)-yl)propan-1-one (25)

Synthesis of 2-[(carboxymethyl)amino]benzoic acid (Intermediate-32)

To a 500 mL 2 neck RB flask fitted with magnetic stirrer, StartingMaterial-16 (20 g, 145 mmol) was added lot wise to a stirred solution ofK₂CO₃ (83 g, 602 mmol) in water (140 mL) followed by chloroacetic acid(13.7 g, 145 mmol) under N₂ atmosphere at room temperature for about 30minutes. Then reaction mass was heated at 90° C. for 16 hours. After thereaction was cooled to room temperature the reaction mass pH wasadjusted to 4-5 using citric acid. The solid material was then filteredand dried under vacuum oven at 70° C. for 12 hours to giveIntermediate-32 (23 g) as brownish solid.

Synthesis of 1-acetyl-1H-indol-3-yl acetate (Intermediate-33)

To a 500 mL 2 neck RB flask fitted with magnetic stirrer, aceticanhydride (110 mL, 1200 mmol) was added slowly at 0° C. to a stirredsolution of triethylamine (170 mL, 1242 mmol) and Intermediate-32 (23 g,117 mmol) under N₂ atmosphere. Reaction mass was stirred at roomtemperature for 5 hours and was further heated at 80° C. for 16 hours.Then the reaction was cooled to 0° C. and was extracted with ethylacetate (4×150 mL). Organic layer was washed with brine solution, driedover Na₂SO₄ and concentrated. Crude material was purified by silica gelcolumn eluting with hexanes: EtOAc to give Intermediate-33 (5.5 g) asbrown solid.

Synthesis of 1-(3-hydroxy-1H-indol-1-yl)ethanone (Intermediate-34)

To a 50 mL 2 neck RB flask fitted with magnetic stirrer, ethanol andwater was added. To the solvent, the stirred mixture of Intermediate-33(5 g, 23 mmol), Na₂SO₃ (11.6 g, 426 mmol) was added. The reactionmixture was heated at 80° C. for 12 hours. After completion of reaction(reaction monitored by TLC), reaction mass was quenched with water andextracted with Ethyl Acetate (3×100 mL). The organic layer was washedwith saturated brine solution (15 mL), dried over anhydrous Na₂SO₄, andconcentrated. The crude product was purified by silica gel columneluting with hexanes: EtOAc to give Intermediate-34 (1.5 g) as pinksolid.

Synthesis of 2-chloro-1-(octahydroquinolin-1(2H)-yl)propan-1-one(Intermediate-35)

To a 50 mL 2 neck RB flask fitted with magnetic stirrer containingreaction mixture of Starting Material-4 (0.7 g, 5 mmol), EDCI (1.17 g,6.3 mmol) and 1-hydroxy benzothioazole (0.762 g, 5.6 mmol) in DCM at 0°C., triethylamine (1.3 mL, 9.9 mmol), was added followed by addition of2-chloropropanoic acid (0.543 g, 5 mmol). Resulted reaction mixture wasstirred at room temperature for 16 hours. After completion of reaction(reaction monitored by TLC), reaction mass was quenched with water andextracted with DCM (3×25 mL). The organic layer was washed withsaturated brine solution (15 mL), dried over anhydrous Na₂SO₄, andconcentrated. The crude product was purified by silica gel columneluting with hexanes: EtOAc to give Intermediate-35 (0.5 g) as liquidmaterial.

Synthesis of2-[(1-acetyl-1H-Indol-3-yl)oxy]-1-(octahydroquinolin-1(2H)-yl)propan-1-one(Intermediate-36)

To a 50 mL 2 neck RB flask fitted with magnetic stirrer Intermediate-34(0.05 g, 0.28 mmol) and DMSO (3 ml) were added at 0° C. under nitrogenatmosphere. To this Potassium t-Butoxide (0.05 g, 0.46 mmol) was addedand stirred for 1 hour, then Intermediate-35 (0.065 g, 0.28 mmol) wasadded. Resulting mixture stirred at room temperature for 16 hours. Afterreaction (reaction monitored by TLC), quenched with water and extractedwith ethyl acetate (3×10 mL). The organic layer was washed withsaturated brine solution (10 mL), dried over anhydrous Na₂SO₄, andconcentrated to give Intermediate-36 (100 mg).

Synthesis of Compound (25)

To a stirred solution of Intermediate-36 (0.1 g, 0.27 mmol) in methanoland water was added K₂CO₃ (0.15 g, 1.0 mmol), and stirred at roomtemperature for 3 hours. After completion of the reaction (reactionmonitored by TLC), quenched with water and extracted with ethyl acetate(3×10 mL). The organic layer was washed with saturated brine solution(15 mL), and concentrated. The crude product was purified by silica gelcolumn eluting with hexanes: EtOAc to give Compound (25) (6 mg) as asticky solid. ¹H NMR (300 MHz, CDCl3): δ 7.55-7.58 (d, 2H), 7.19-7.22(d, 1H), 7.08-7.013 (t, 1H), 6.98-7.02 (t, 1H), 6.67-6.68 (d, 1H),4.75-4.85 (m, 1H), 4.10-4.56 (m, 2H), 2.52-2.96 (m, 1H), 1.18-1.60 (m,16H). LC-MS (M+H)⁺=327.2; HPLC purity: 99.99%.

Example 26 1-[3-(1H-indol-3-yl)propanoyl]octahydroquinolin-4(1H)-one(26)

Synthesis of 1-(cyclohex-1-en-1-yl)-3-(dimethylamino)propan-1-one(Intermediate-37)

Starting Material-17 (5 g, 40.3 mmol), dimethyl amine hydrochloride(3.62 g, 44.3 mmol), paraformaldehyde (2.42 g, 80.5 mmol), 37% aqueousHCl (0.2 mL, 40.3 mmol) were combined in ethanol (5 mL). The resultantmixture was heated to reflux in a sealed tube for 20 hours. The reactionwas then concentrated, basified with aq. NaOH and extracted with CHCl3.The combined organic layers were dried over Na₂SO₄, concentrated to giveIntermediate-37 (4.78 g) as light orange oily material.

Synthesis of tert-butyl 4-oxooctahydroquinolin-1(2H)-carboxylate(Intermediate-38)

Intermediate-37 (4.2 g, 23.2 mmol), was taken in 1,4-dioxane (3 mL), andconcentrated NH₄OH (5 mL) in a sealed tube. The vessel was sealed andthen heated in an oil bath at 120° C. for 18 hours. Then reactionmixture was cooled to room temperature, and concentrated. The residuewas taken up in CHCl₃, dried over Na₂SO₄ and concentrated to give crudematerial (3.35 g). This crude material was treated with Boc₂O (4.8 g,29.8 mmol), in presence of TEA (9 mL, 64.5 mmol), in THF (10 mL) at roomtemperature for 16 hours. After completion of reaction, the reactionmixture was diluted with water, extracted with EtOAc and concentrated togive crude material, which is purified by silica gel columnchromatography eluting with hexanes: EtOAc to give Intermediate-38 (1.34g).

Synthesis of octahydroquinolin-4(1H)-one trifluoroacetic acid salt(Intermediate-39)

At 0° C., Trifluoro acetic acid (0.162 g, 1.42 mmol) was added drop wiseto a solution of Intermediate-38 (0.3 g, 1.18 mmol) in DCM (3 mL), undernitrogen atmosphere. Resultant mixture was stirred at RT for 16 h. Aftercompletion the reaction mixture was concentrated to give Intermediate-39(352 mg).

Synthesis of Compound (26)

Compound (26) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(26). ¹H NMR (300 MHz, CDCl3): δ 8.05 (s, 1H), 7.53-7.58 (t, 1H),7.27-7.29 (d, 1H), 7.02-7.19 (m, 2H), 6.98 (s, 1H), 4.60-4.92 (m, 1H),3.69-3.83 (m, 1H), 306-3.37 (m, 3H), 2.63-2.92 (m, 2H), 1.35-2.25 (m,11H). LC-MS (M+H)⁺=325.2; HPLC purity: 93.87%.

Example 273-(1,4-dimethyl-1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one(27)

Synthesis of Compound (27)

Under N₂ atmosphere to a stirred solution of (20) (70 mg 0.2157 mmol) in5 mL of dry THF, sodium hydride (22 mg, 0.5394 mmol) was added, andstirred for 30 minutes at room temperature. To this reaction mixturemethyl iodide (77 mg, 0.5394 mmol) was added at 0° C. The mixture wasstirred at room temperature for 3 hours. The mixture was quenched withcrushed ice and extracted with ethyl acetate, and concentrated.Resulting crude material was purified by silica-gel columnchromatography eluting with hexanes: EtOAc to give Compound (27) (55mg). ¹H NMR (300 MHz, CDCl3): δ 6.98-7.03 (m, 2H), 6.76-6.78 (m, 2H),3.47-4.63 (m, 1H), 3.62-3.63 (d, 3H), 3.15-3.20 (m, 2H), 2.63-2.92 (m,4H), 2.46-2.60 (m, 2H), 1.23-1.93 (m, 14H). LC-MS (M+H)⁺=339.2; HPLCpurity: 99.79%.

Example 283-(1-cyclopropyl-4-methyl-1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one (28)

Synthesis of Compound (28)

Compound (28) was synthesized by following the procedure used to makeCompound (27) (Scheme 26). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(28). ¹H NMR (300 MHz, CDCl3): δ 6.96-7.04 (m, 2H), 6.80-6.81 (m, 1H),6.64-6.67 (m, 1H), 5.34-5.41 (m, 1H), 4.49-4.63 (m, 1H), 3.49-3.63 (m,1H), 3.18-3.22 (m, 2H), 2.64-2.74 (m, 4H), 2.46-2.60 (m, 2H), 1.23-1.80(m, 17H). LC-MS (M+H)⁺=365.3; HPLC purity: 98.79%.

Example 293-[1-(cyclopropylmethyl)-4-methyl-1H-indol-3-yl]-1-(octahydroquinolin-1(2H)-yl)propan-1-one(29)

Synthesis of Compound (29)

Compound (29) was synthesized by following the procedure used to makeCompound (27) (Scheme 26). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(29). ¹H NMR (300 MHz, CDCl3): δ 7.08-7.10 (d, 1H), 6.97-7.02 (m, 1H),6.91-6.93 (d, 1H), 6.75 (m, 1H), 4.45-4.63 (m, 1H), 3.81-3.83 (d, 2H),3.45-3.58 (m, 1H), 3.16-3.21 (m, 2H), 2.49-2.77 (m, 6H), 1.23-1.97 (m,14H), 0.51-0.54 (m, 2H), 0.26-0.27 (m, 2H). LC-MS (M+H)⁺=379.3; HPLCpurity: 99.43%.

Example 301-(4-methyl-1H-indol-3-yl)-3-(octahydroquinolin-1(2H)-yl)propane-1,3-dione(30)

Synthesis of Compound (30)

Compound (30) was synthesized by following the procedure used to makeCompound (19) (Scheme 20). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(30). ¹H NMR (300 MHz, CDCl3): δ 9.25-9.31 (d, 1H), 8.26-8.30 (m, 1H),7.06-7.15 (m, 2H), 6.95-6.97 (d, 1H), 4.12-4.60 (m, 1H), 3.90 (s, 2H),3.59-4.16 (m, 1H), 2.52-3.06 (m, 1H), 2.75-2.76 (d, 3H), 1.93-2.30 (m,1H), 1.26-1.98 (m, 12H). LC-MS (M+H)⁺=339.2; HPLC purity: 98.52%.

Example 31(2E)-3-(1H-indol-3-yl)-2-(octahydroquinolin-1(2H)-ylcarbonyl)prop-2-enenitrile(31)

Synthesis of tert-butyl3-[(1Z)-2-cyano-3-ethoxy-3-oxoprop-1-en-1-yl]-1H-indole-1-carboxylate(Intermediate-40)

A 50 mL RB flask fitted with magnetic stirrer was charged withisoproponol (10 mL) and Starting Material-18. To this ethyl cyanoacetate (0.255 g, 2.2 mmol) and potassium hydroxide (0.12 g, 2.2 mmol)were added at 0° C. and was stirred for 1 hour. After completion of thereaction (reaction monitored by TLC), reaction mixture was quenched withIce-Water 350 mL and extracted with ethyl acetate. The organic layerwashed with brine solution and dried by anhydrous sodium sulphate andconcentrated to give Intermediate-40 (600 mg).

Synthesis of (2Z)-2-cyano-3-(1H-indol-3-yl)prop-2-enoic acid(Intermediate-41)

A 100 mL RB flask fitted with magnetic stirrer was charged with 5 mL ofEthanol and Intermediate-40 (0.6 g, 1.7 mmol). To this NaOH (0.20 g, 2.4mmol) in 0.5 mL of water was added and the reaction mixture was stirredat room temperature for 3 hours. After completion of the reaction(reaction monitored by TLC), the reaction mixture was concentrated. Theresulted crude was acidified with 1N HCl (pH 1-2), and extracted withethyl acetate. Organic layers were washed with brine solution and driedby anhydrous sodium sulphate and concentrated to giveIntermediate-41(400 mg).

Synthesis of Compound (31)

Compound (31) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(31). ¹H NMR (300 MHz, CDCl3): δ 8.94 (s, 1H), 8.44 (s, 1H), 8.13 (s,1H), 7.68-7.71 (d, 1H), 7.37-7.40 (d, 1H), 7.21-7.26 (m, 2H), 4.30-4.48(m, 1H), 3.90-4.08 (m, 1H), 2.75-3.18 (m, 1H), 1.30-1.86 (m, 13H). LC-MS(M+H)⁺=334.2; HPLC purity: 94.91%.

Example 321-[3-(4-methyl-1H-indol-3-yl)propanoyl]octahydroquinolin-4(1H)-one (32)

Synthesis of Compound (32)

Compound (32) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(32). ¹H NMR (300 MHz, CDCl3): δ 7.92 (s, 1H), 7.11-7.14 (d, 1H),6.95-6.99 (m, 2H), 6.79 (s, 1H), 4.62-4.94 (m, 1H), 4.04-4.06 (d, 3H),3.57-3.87 (m, 1H), 3.25-3.39 (m, 2H), 2.57-2.66 (m, 4H), 1.43-2.26 (m,10H). LC-MS (M+H)⁺=339.2; HPLC purity: 92.86%.

Example 333-(1-ethyl-4-methyl-1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one(33)

Synthesis of Compound (33)

Compound (33) was synthesized by following the procedure used to makeCompound (27) (Scheme 26). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(33). ¹H NMR (300 MHz, CDCl3): δ 6.98-7.08 (m, 2H), 6.83-6.84 (d, 1H),6.75-6.77 (m, 1H), 4.45-4.63 (m, 1H), 3.98-4.05 (m, 2H), 3.47-3.57 (m,1H), 3.16-3.20 (t, 2H), 2.50-2.92 (m, 6H), 1.23-1.76 (m, 16H). LC-MS(M+H)⁺=353.3

Example 341-(4-hydroxy-4-methyloctahydroquinolin-1(2H)-yl)-3-(1H-indol-3-yl)propan-1-one(34)

Synthesis of tert-butyl4-hydroxy-4-methyloctahydroquinoline-1(2H)-carboxylate (Intermediate-42)

In a 50 mL-2 neck-RB flask fitted with magnetic sitter, a 3.0 M solutionof methyl magnesium iodide in ether (1.45 mL, 4.4 mmol) was added dropwise at −20° C. to a stirred solution of Intermediate-38 (0.55 g, 2.2mmol) in 5 ml of dry THF under N₂ atmosphere. Resulting mixture wasstirred at room temperature for 16 hours. After completion of thereaction (monitored by TLC), the reaction mixture was quenched with icewater and extracted with ethyl acetate (3×15 ml). Organic layer waswashed with brine solution and dried over Na₂SO₄ and concentrated. Crudematerial was purified by silica-gel column chromatography eluting withhexanes: EtOAc to give Intermediate-42 (82 mg) as gummy solid. LC-MS(M+H)+=270.1.

Synthesis of -methyldecahydroquinolin-4-ol trifluoroacetic acid salt(Intermediate-43)

Intermediate-43 was synthesized by following the procedure used to makeIntermediate-39 (Scheme 25).

Synthesis of Compound (34)

Compound (34) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(34). ¹H NMR (300 MHz, CDCl3): δ 7.95 (s, 1H), 7.54-7.56 (d, 1H),7.27-7.29 (d, 1H), 7.02-7.14 (m, 2H), 6.97 (s, 1H), 4.38-4.53 (m, 1H),3.39-3.42 (m, 1H), 3.06-3.08 (m, 2H), 2.51-2.77 (m, 2H), 0.86-2.10 (m,16H). LC-MS (M+H)⁺=341.2; HPLC purity: 80.53%.

Example 353-(4-methyl-1H-indol-3-yl)-1-(2-methyloctahydroquinolin-1(2H)-yl)propan-1-one(35)

Synthesis of Compound (35)

Compound (35) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(35). ¹H NMR (300 MHz, CDCl3): δ 7.90 (s, 1H), 7.10-7.13 (d, 1H),6.92-7.01 (m, 2H), 6.79 (m, 1H), 4.48-4.71 (m, 1H), 3.48-3.94 (m, 1H),3.19-3.24 (t, 2H), 2.48-2.79 (m, 6H), 1.09-1.77 (m, 15H). LC-MS(M+H)⁺=339.3; HPLC purity: 98.23%.

Example 363-(1H-indol-3-yl)-1-[(4E)-4-(methoxyimino)decahydronaphthalen-1-yl]propan-1-one(36)

Synthesis of tert-butyl(4E)-4-(methoxyimino)octahydroquinoline-1(2H)-carboxylate(Intermediate-44)

In a 50 mL-2 neck-RB flask fitted with magnetic sitter, pyridine (0.45mL, 3 vol) was added to a stirred solution of Intermediate-38 (150 mg,0.596 mmol) in ethanol (1.5 ml, 8 vol). To this O-methoxylaminehydrochloride (250 mg, 2.96 mmol) was added. The resulting mass wasrefluxed at 90° C. for 3 hours. After completion of reaction (monitoredby TLC), the solvent was completely removed from the reaction mass undervacuum. Crude was portioned between water and ethyl acetate. The organiclayer was separated and the aqueous layer thus obtained was washed withethyl acetate and concentrated. Resulted crude material was purified bysilica-gel column chromatography eluted with hexanes: EtOAc to giveIntermediate-44 (150 mg) as pale greenish liquid material.

Synthesis of (4E)-N-methoxyoctahydroquinolin-4(1H)-imine trifluoroaceticacid salt (Intermediate-45)

Intermediate-45 was synthesized by following the procedure used to makeIntermediate-39 (Scheme 25).

Synthesis of Compound (36)

Compound (36) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(36). ¹H NMR (300 MHz, CDCl3): δ 7.95 (s, 1H), 7.52-7.54 (m, 1H),7.27-7.30 (m, 1H), 7.02-7.15 (m, 2H), 6.97 (s, 1H), 4.10-4.67 (m, 1H),3.76 (d, 3H), 3.18-3.59 (m, 1H), 3.04-3.17 (m, 2H), 2.54-2.86 (m, 3H),1.35-2.26 (m, 11H). LC-MS (M+H)⁺=354.2; HPLC purity: 88.00%.

Example 373-(1H-indol-3-yl)-1-(3-methyloctahydroquinolin-1(2H)-yl)propan-1-one(37)

Synthesis of Compound (37)

Compound (37) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(37). ¹H NMR (300 MHz, DMSO-d6): δ 10.76 (s, 1H), 7.49-7.52 (d, 1H),7.30-7.33 (d, 1H), 7.02-7.12 (m, 2H), 6.94-6.99 (t, 1H), 4.00-4.60 (m,1H), 3.37-3.66 (m, 1H), 3.01-3.19 (m, 1H), 2.87-2.95 (m, 2H), 2.54-2.78(m, 2H), 0.30-1.98 (m, 15H). LC-MS (M+H)⁺=325.2; HPLC purity: 97.66%.

Example 383-(1H-indol-3-yl)-1-(2-methyloctahydroquinolin-1(2H)-yl)propan-1-one(38)

Synthesis of Compound (38)

Compound (38) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(38). ¹H NMR (300 MHz, CDCl3): δ 8.05 (s, 1H), 7.54-7.57 (m, 1H),7.27-7.30 (d, 1H), 7.04-7.18 (m, 2H), 6.96 (s, 1H), 4.48-4.87 (m, 1H),3.26-4.09 (m, 1H), 3.05-3.10 (m, 2H), 2.50-2.81 (m, 2H), 0.90-1.80 (m,16H). LC-MS (M+H)⁺=325.2; HPLC purity: 98.14%.

Example 393-(6-fluoro-1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one(39)

Synthesis of Compound (39)

Compound (39) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate (1:4) as eluent to obtainCompound (39). ¹H NMR (300 MHz, CDCl3): δ 7.92 (s, 1H), 7.41-7.47 (m,1H), 6.94-6.98 (m, 2H), 6.78-6.84 (m, 1H), 4.30-4.60 (m, 1H), 3.30-3.60(m, 1H), 3.10-3.30 (m, 3H), 2.49-2.68 (m, 2H), 1.16-1.66 (m, 13H). LC-MS(M+H)⁺=329.2

Example 403-(6-fluoro-1H-indol-3-yl)-1-(2-methyloctahydroquinolin-1(2H)-yl)propan-1-one(40)

Synthesis of Compound (40)

Compound (40) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(40). ¹H NMR (300 MHz, CDCl3): δ 7.98 (s, 1H), 7.41-7.47 (m, 1H),6.94-6.98 (d, 2H), 6.78-6.84 (m, 1H), 4.47-4.71 (m, 1H), 3.37-3.90 (m,1H), 3.02-3.07 (t, 2H), 2.46-2.77 (m, 2H), 0.91-1.82 (m, 16H). LC-MS(M+H)⁺=343.22; HPLC purity: 97.64%.

Example 41 3-(1H-indol-3-yl)-1-(octahydro-1H-Indol-1-yl)propan-1-one(41)

Synthesis of octahydro-1H-indole (Intermediate-46)

Intermediate-46 was synthesized by following the procedure used to makeIntermediate-18 (Scheme 13).

Synthesis of Compound (41)

Compound (41) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(41). ¹H NMR (300 MHz, CDCl3): δ 8.02 (s, 1H), 7.53-7.56 (d, 1H),7.27-7.30 (d, 1H), 7.02-7.14 (m, 2H), 6.96 (s, 1H), 3.29-4.03 (m, 3H),3.03-3.23 (m, 2H), 2.49-2.70 (m, 2H), 0.88-2.07 (m, 11H). LC-MS(M+H)⁺=297.22; HPLC purity: 99.0%.

Example 42 3-(1H-indol-3-yl)-1-(octahydro-2H-isoindol-2-yl)propan-1-one(42)

Synthesis of Compound (42)

Compound (42) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(42). ¹H NMR (300 MHz, CDCl3): δ 7.98 (s, 1H), 7.53-7.56 (d, 1H),7.27-7.30 (d, 1H), 6.99-7.13 (m, 3H), 3.28 (s, 2H), 3.13 (m, 3H), 2.94(s, 1H), 2.63-2.68 (t, 2H), 2.24 (s, 3H), 2.02 (s, 2H), 1.31 (m, 5H).LC-MS (M+H)⁺=297.2; HPLC purity: 97.66%.

Example 431-[3-(6-fluoro-1H-indol-3-yl)propanoyl]octahydroquinolin-4(1H)-one (43)

Synthesis of Compound (43)

Compound (43) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate (1:4) as eluent to obtainCompound (43). ¹H NMR (300 MHz, CDCl3): δ 8.14 (s, 1H), 7.42-7.43 (m,1H), 6.95 (s, 1H), 6.67-6.84 (m, 2H), 4.62-4.91 (m, 1H), 3.71-3.81 (m,1H), 2.78-3.42 (m, 4H), 2.69 (m, 2H), 1.28-2.47 (m, 10H). LC-MS(M+H)⁺=343.2; HPLC purity: 96.03%.

Example 443-(4-fluoro-1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one(44)

Synthesis of Compound (44)

Compound (44) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(44). ¹H NMR (300 MHz, DMSO-d6): δ 11.07 (s, 1H), 7.14-7.17 (m, 2H),6.99-7.01 (m, 1H), 6.66-6.75 (m, 1H), 4.29-4.48 (m, 1H), 3.63-3.76 (m,1H), 2.95-2.97 (m, 2H), 2.56-2.76 (m, 3H), 1.66-1.75 (m, 5H), 1.52-1.61(m, 2H), 1.28-1.45 (m, 6H). LC-MS (M+H)⁺=329.3; HPLC purity: 97.26%.

Example 453-(1H-indol-3-O-1-(2-methyloctahydro-1H-indol-1-yl)propan-1-one (45)

Synthesis of Compound (45)

Compound (45) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(45). ¹H NMR (300 MHz, CDCl3): δ 8.00 (s, 1H), 7.54-7.56 (d, 1H),7.28-7.30 (d, 1H), 7.02-7.14 (m, 2H), 6.97 (s, 1H), 3.86-4.10 (m, 1H),3.29-3.65 (m, 1H), 3.01-3.20 (m, 2H), 2.57-2.72 (m, 2H), 2.04 (s, 3H),1.72-1.86 (m, 2H), 1.55-1.66 (m, 3H), 1.03-1.35 (m, 6H). LC-MS(M+H)⁺=311.2; HPLC purity: 99.27%.

Example 46{3-[3-(octahydroquinolin-1(2H)-yl)-3-oxopropyl]-1H-indol-1-yl}aceticacid (46)

Synthesis of ethyl{3-[3-(octahydroquinolin-1(2H)-yl)-3-oxopropyl]-1H-Indol-1-yl}acetate(Intermediate-47)

Intermediate-47 was synthesized by following the procedure used to makeIntermediate-24 (Scheme 19).

Synthesis of Compound (46)

Compound (46) was synthesized by following the procedure used to makeIntermediate-3 (Scheme 1). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(46). ¹H NMR (300 MHz, CDCl3): δ 7.46-7.50 (t, 1H), 7.02-7.18 (m, 3H),6.80 (s, 1H), 4.66 (s, 2H), 4.39-4.58 (m, 1H), 3.47-3.60 (m, 1H),2.93-3.01 (m, 2H), 2.44-2.85 (m, 4H), 1.25-1.65 (m, 13H). LC-MS(M+H)⁺=369.22; HPLC purity: 93.09%.

Example 473-(4-fluoro-1-methyl-1H-Indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one(47)

Synthesis of Compound (47)

Compound (47) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(47). ¹H NMR (300 MHz, CDCl3): δ 7.20-7.23 (d, 1H), 7.14 (s, 1H),7.05-7.11 (m, 1H), 6.71-6.79 (1H), 4.29-4.48 (m, 1H), 3.62-3.79 (m, 4H),2.92-2.98 (m, 2H), 2.61-2.72 (m, 3H), 1.35-1.75 (m, 13H). LC-MS(M+H)⁺=343.3; HPLC purity: 98.84%.

Example 481-(3,4,5,6,7,8-hexahydroquinolin-1(2H)-yl)-3-(1H-indol-3-yl)propan-1-one(48)

Synthesis of Compound (48)

Compound (48) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(48). ¹H NMR (300 MHz, CDCl3): 8.00 (s, 1H), 7.51-7.54 (d, 1H),7.26-7.29 (d, 1H), 7.01-7.18 (m, 2H), 6.94 (s, 1H), 3.37 (s, 2H),3.03-3.08 (t, 2H), 2.65-2.70 (t, 2H), 2.30-2.39 (m, 1H), 1.87 (s, 3H),1.79 (s, 2H), 1.53-1.59 (m, 6H). LC-MS (M+H)⁺=309.25; HPLC purity:85.06%.

Example 49 methyl1-[3-(1H-indol-3-yl)propanoyl]decahydroquinoline-4-carboxylate (49)

Synthesis of decahydroquinoline-4-carboxylic acid (Intermediate-48)

Intermediate- was synthesized by following the procedure used to makeIntermediate-18 (Scheme 13).

Synthesis of methyl decahydroquinoline-4-carboxylate (Intermediate-49)

To a stirred solution of Intermediate-48 (800 mg g, 4.3656 mmol) inmethanol (30 mL) thionyl chloride (0.48 mL, 6.5483 mmol) was added undernitrogen atmosphere at 0° C. The mixture was stirred at room temperaturefor 16 hours. After completion of the reaction, the reaction mixture wasconcentrated to give Intermediate-49 (775 mg).

Synthesis of Compound (49)

Compound (49) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(49). ¹H NMR (300 MHz, CDCl3): δ 7.97 (s, 1H), 7.54-7.56 (d, 1H),7.27-7.30 (d, 1H), 7.02-7.14 (m, 2H), 6.97 (s, 1H), 3.73-4.08 (m, 1H),3.59 (s, 3H), 3.28-3.53 (m, 1H), 3.04-3.09 (t, 2H), 2.46-2.74 (m, 3H),0.91-2.03 (m, 12H). LC-MS (M+H)⁺=369.2; HPLC purity: 96.44%.

Example 50 1-[3-(1H-indol-3-yl)propanoyl]decahydroquinoline-4-carboxylicacid (50)

Synthesis of Compound (50)

Compound (50) was synthesized by following the procedure used to makeIntermediate-3 (Scheme 1). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(50). ¹H NMR (300 MHz, DMSO-d6): δ 12.26 (s, 1H), 10.77 (s, 1H),7.50-7.52 (d, 1H), 7.30-7.33 (d, 1H), 7.13 (s, 1H), 6.94-7.07 (m, 2H),3.69-4.53 (m, 1H), 2.89-2.94 (t, 2H), 2.42-2.74 (m, 3H), 1.27-1.91 (m,13H). LC-MS (M+H)⁺=355.2.

Example 511-(octahydroquinolin-1(2H)-yl)-3-[1-(phenylsulfonyl)-1H-indol-3-yl]propan-1-one(51)

Synthesis of Compound (51)

A 100 mL RB flask fitted with magnetic stirrer was charged with 60% NaH(77.26 mg, 1.932 mmol). To this 10 mL of THF was added at 0° C. undernitrogen atmosphere. (96) (200 mg, 0.644 mmol) in THF was then added tothe solvent and stirred at this temperature for 30 minutes. Phenylsulfonyl chloride (170.61 mg, 0.966 mmol) was added and stirred at roomtemperature for 15 hours. After completion of reaction (reactionmonitored by TLC), the reaction mass was quenched with crushed ice,extracted with ether (100 ml×3). The combined ether layer was washedwith water (100 mL×3), brine, dried over anhydrous Na₂SO₄, andconcentrated. Crude material was purified by silica-gel columnchromatography eluting with hexanes: EtOAc to give (170 mg) as yellowsticky solid. ¹H NMR (300 MHz, CDCl3): δ 7.89-7.92 (d, 1H), 7.77-7.81(m, 2H), 7.42-7.46 (m, 2H), 7.13-7.36 (m, 5H), 4.42-4.60 (m, 1H),3.45-3.57 (m, 1H), 2.22-2.43 (m, 5H), 1.54-1.76 (m, 6H), 1.49 (s, 2H),1.27-1.34 (m, 5H). LC-MS (M+H)⁺=451.2; HPLC purity: 93.06%.

Example 52 3-(1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one(Peak-1) (52)

Synthesis of Compound (52) (Peak-1

Compound (96) mixture of isomers was separated by reverse phase columnto give Compound (52) (Peak-1). ¹H NMR (300 MHz, CDCl3): δ 8.13 (s, 1H),7.52-7.55 (d, 1H), 7.26-7.28 (d, 1H), 7.01-7.12 (m, 2H), 6.92-6.93 (d,1H) m, 3.66-3.68 (m, 1H), 2.73-3.09 (m, 5H), 1.94 (s, 2H), 1.21-1.66 (m,12H). LC-MS (M+H)⁺=311.2; HPLC purity: 99.86% (Column: Zorbax eclipseXDB-C18, RT=16.83 min, mobile phase: H₂O:MeCN=55:45).

Example 53 3-(1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one(Peak-2) (53)

Synthesis of Compound (53) (Peak 2

Compound (96) mixture of isomers was separated by reverse phase columnto give compound, Compound (53) (peak 2). ¹H NMR (300 MHz, CDCl3): δ7.89 (s, 1H), 7.53-7.58 (t, 1H), 7.26-7.31 (t, 1H), 7.02-7.14 (m, 2H),6.98 (s, 1H), 4.45-4.62 (m, 1H), 3.47-3.58 (m, 1H), 3.01-3.09 (m, 2H),2.50-2.91 (m, 3H), 1.27-1.67 (m, 13H). LC-MS (M+H)⁺=311.1; HPLC purity:99.80% (Column: Zorbax eclipse XDB-C18, RT=17.87 min, mobile phase:H₂O:MeCN=55:45).

Example 541-(decahydro-1H-1-benzazepin-1-yl)-3-(1H-indol-3-yl)propan-1-one (54)

Synthesis of Compound (54)

Compound (54) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(54). ¹H NMR (300 MHz, CDCl3): δ 7.93 (s, 1H), 7.53-7.57 (t, 1H),7.27-7.30 (d, 1H), 7.02-7.14 (m, 2H), 6.97 (s, 1H), 4.13-4.70 (m, 1H),3.35-3.62 (m, 1H), 3.05-3.17 (m, 2H), 2.53-2.81 (m, 3H), 1.29-1.81 (m,15H). LC-MS (M+H)⁺=325.2; HPLC purity: 98.41%.

Example 553-(1H-indol-3-yl)-1-(4a-methyloctahydroquinolin-1(2H)-yl)propan-1-onePeak-1 (55)

Synthesis of Compound (55) (Peak 1

Mixture of isomers were separated by silica gel column chromatographyeluting with hexanes: EtOAc to give Compound (55) (peak 1). ¹H NMR (300MHz, CDCl3): δ 7.92 (s, 1H), 7.53-7.55 (d, 1H), 7.28-7.31 (d, 1H),7.04-7.15 (m, 2H), 6.97 (s, 1H), 4.25-4.54 (m, 1H), 3.24-3.52 (m, 1H),3.03-3.08 (m, 2H), 2.58-2.76 (m, 3H), 0.83-1.94 (m, 15H). LC-MS(M+H)⁺=325.2; HPLC purity: 91.22%; Column: Zorbax eclipse XDB-C18,RT=17.43 min, mobile phase: H₂O: MeCN: TFA (0.01%) gradient.

Example 563-(1H-indol-3-yl)-1-(4a-methyloctahydroquinolin-1(2H)-yl)propan-1-onePeak-2 (56)

Synthesis of Compound (56) (Peak 2

Mixture of isomers were separated by silica gel column chromatographyeluting with hexanes: EtOAc to give Compound (56) (Peak-2). ¹H NMR (300MHz, CDCl3): δ 7.93 (s, 1H), 7.53-7.55 (d, 1H), 7.27-7.30 (d, 1H),7.01-7.14 (m, 2H), 6.96 (s, 1H), 3.80-4.61 (m, 1H), 3.25-3.60 (m, 1H),2.99-3.05 (m, 2H), 2.59-2.78 (m, 4H), 0.83-1.93 (m, 14H). LC-MS(M+H)⁺=325.2; HPLC purity: 97.45%; Zorbax eclipse XDB-C18, RT=18.36 min,mobile phase: H2O: MeCN: TFA (0.01%) gradient.

Example 572-(1H-indol-3-ylsulfonyl)-1-(octahydroquinolin-1(2H)-yl)ethanone (57)

Synthesis of Compound (57)

To a stirred solution of (5) (100 mg, 0.30 mmol) in DCM (5 mL) was addedm-CPBA (78 mg, 0.45 mmol) and stirred at rt for 16 hours. Aftercompletion of reaction (reaction monitored by TLC), the reaction mixturewas quenched with saturated NaHCO₃ solution, extracted with DCM andconcentrated. The crude product was purified by silica gel column usingPetroleum ether: Ethyl acetate as eluent to obtain Compound (57) (50 mg)as yellow solid. ¹H NMR (300 MHz, CDCl3): δ 9.95 (s, 1H), 7.81-7.84 (d,1H), 7.49 (s, 1H), 7.10-7.15 (m, 3H), 3.85-4.43 (m, 3H), 2.56-3.28 (m,1H), 1.16-1.86 (m, 14H). LC-MS (M+H)⁺=361.1; HPLC purity: 98.60%.

Example 583-methyl-3-(1-methyl-1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)butan-1-one(58)

Synthesis of 2-methyl-2-(1-methyl-1H-indol-3-yl)propan-1-ol(Intermediate-50)

A 250 mL RB flask fitted with magnetic stirrer was charged with Lithiumaluminum hydride (0.983 g, 25.951 mmol) and THF (20 mL) was added to itat 0° C. To this resulting suspension Intermediate-5 (2.0 g, 8.65 mmol)in THF (20 mL) was added and the resulting mixture was stirred at roomtemperature for 2 hours. After completion of the reaction, the reactionmixture was diluted with EtOAc (50 mL) and was quenched with Na₂SO₄ (5g) and the resulting slurry was stirred at room temperature for 1 hour,filtered through celite washed with ethyl acetate. The resultingfiltrate was concentrated to give Intermediate-50 (0.9 g). ¹H NMR (300MHz, DMSO-d6): δ 7.65-7.68 (d, 1H), 7.34-7.36 (d, 1H), 7.07-7.12 (0H),7.03 (s, 1H), 6.94-6.99 (t, 1H), 4.53-4.57 (t, 1H), 3.71 (s, 3H),3.54-3.56 (d, 2H), 1.31 (s, 6H).

Synthesis of 2-methyl-2-(1-methyl-1H-indol-3-yl)propanal(Intermediate-51)

A 100 mL RB flask fitted with magnetic stirrer was charged with 30 mLDCM and Pyridinium chloro chromate (2.466 g, 11.4419 mmol) was addedfollowed by the addition of Intermediate-50 (1.55 g, 7.627 mmol) in 10mL of DCM. The resulting mixture was stirred at room temperature for 2hours. After completion of the reaction, the solvent from the reactionmass was removed under reduced pressure to yield the crude compound.Crude mass was purified by column chromatography using 60-120 silica geland 9:1 Pet ether/ethyl acetate as eluent to give Intermediate-51 (0.79g). ¹H NMR (300 MHz, DMSO-d6): δ 9.39 (s, 1H), 7.40-7.44 (t, 1H), 7.32(s, 1H), 7.13-7.18 (t, 1H), 6.98-7.03 (t, 1H), 3.77 (s, 3H), 1.46 (s,H).

Synthesis of 3-[(3E)-4-methoxy-2-methylbut-3-en-2-yl]-1-methyl-1H-Indole(Intermediate-52)

A 100 mL RB flask fitted with magnetic stirrer was charged with 20 mL ofdry THF and Methoxy methyl triphenyl phosphonium chloride (2.566 g,7.487 mmol) was added followed by addition of Pot tea butoxide (2.295 g,20.451 mmol). The resulting mass was stirred at room temperature for 2hours and then cooled to 0° C. Intermediate-51 (1.37 g, 6.807 mmol) in10 mL of THF was added to the above reaction mass and was stirred atroom temperature for 2 hours. After completion of the reaction (by TLC)reaction mass was diluted with 10 mL of water and was extracted withethyl acetate (100 mL×3) and the combined organic layers were washedwith brine solution and was dried over anhydrous sodium sulfateconcentrated. Crude product was purified by column chromatography using60-120 silica gel and 6% of ethyl acetate in Pet ether as eluent to giveIntermediate-52. Yield: 1.12 g (71.8%). ¹H NMR (300 MHz, CDCl3): δ7.73-7.80 (m 1H), 7.33 (s, 1H), 7.16-7.21 (t, 1H), 7.03-7.08 (t, 1H),6.81 (s, 1H), 5.79-6.34 (m, 1H), 4.58-5.15 (m, 1H), 3.73-3.74 (d, 3H),3.49-3.53 (d, 3H), 1.55 (s, 6H).

Synthesis of 3-methyl-3-(1-methyl-1H-indol-3-yl)butanal(Intermediate-53)

A 100 mL RB flask fitted with magnetic stirrer was charged with 50.4 mLof 1,4 dioxane and 12.76 mL of water. To this Intermediate-52 (1.12 g,4.884 mmol) followed by p-toluene sulphonic acid (0.0424 g, 0.2232 mmol)was added. The resulting mass was heated at 60° C. for 16 hours. Aftercompletion of the reaction, the reaction mixture was quenched with 10 mLof water and extracted with ethyl acetate (100 mL×3) and the combineorganic layer was washed with saturated sodium bicarbonate solutionfollowed by brine solution and was dried over anhydrous sodium sulfateand concentrated. Crude product was purified by column chromatographyusing 60-120 silica gel and 8% of ethyl acetate in Pet ether as eluentto give Intermediate-53. ¹H NMR (300 MHz, DMSO-d6): δ 9.47-9.49 (t, 1H),7.73-7.76 (d, 1H), 7.37-7.40 (d, 1H), 7.11-7.16 (t, 1H), 7.10 (s, 1H),6.99-7.04 (t, 1H) 3.72 (s, 3H), 2.78 (s, 2H), 1.49 (s, 6H).

Synthesis of 3-methyl-3-(1-methyl-1H-indol-3-yl)butanoic acid(Intermediate-54)

A 50 mL RB flask fitted with magnetic stirrer was charged with 10 mL ofTHF and was cooled to −78° C. to which 2-methyl 2 butene (3 mL) wasadded and stirred for 15 minutes. Another 100 mL RB flask fitted withmagnetic stirrer was charged with Intermediate-53 (557 mg, 2.59 mmol)and tert butanol (15 mL) and was stirred at RT and the above preparedTHF solution was added to it. Then the resulting mass was cooled to 0°C. to which NaH₂PO₄ (1.42 g) in water was added followed by addition ofNaClO₂ (0.35 g) in water. The resulting mixture was stirred at 0° C. for20 minutes and quenched with water and pH adjusted to 1-2 using 1N HCland extracted with ethyl acetate and concentrated to giveIntermediate-54 (480 mg). ¹H NMR (300 MHz, DMSO-d6): δ 11.82 (s, 1H),7.69-7.71 (d, 1H), 7.35-7.38 (d, 1H), 7.09-7.14 (t, 1H), 7.05 (s, 1H),6.96-7.01 (t, 1H), 3.71 (s, 3H), 2.66 (s, 2H), 1.48 (s, 6H).

Synthesis of Compound (58)

Compound (58) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(58). ¹H NMR (300 MHz, CDCl3): δ 7.72-7.74 (d, 1H), 7.20-7.23 (d, 1H),7.11-7.16 (t, 1H), 7.03 (s, 1H), 6.76 (s, 1H), 4.34-4.53 (m, 1H), 3.65(s, 1H), 3.07-3.29 (2H), 2.75-2.84 (m, 2H), 2.75-2.84 (m, 2H), 2.27-2.39(m, 4H), 1.54-1.56 (d, 6H), 1.38-1.43 (m, 3H), 1.07 (m, 2H), 0.09 (m,2H), 0.37-0.65 (m, 2H). LC-MS (M+H)⁺=353.3; HPLC purity: 92.52%.

Example 593-methyl-3-(1-methyl-1H-indol-3-yl)-1-(4a-methyloctahydroquinolin-1(2H)-yl)butan-1-one (59)

Synthesis of 3-(1-methyl-2-oxocyclohexyl)propanenitrile(Intermediate-55)

To a stirred solution of Starting Material-20 (5 g, 44.6 mmol) in 15 mLof DMF, Triton-B (40% solution of Binzyl trimethylammonium hydroxide)(20.5 mL, 49.0 mmol) was added in 10 mL of DMF drop wise at 0° C. undernitrogen atmosphere. The mixture was stirred at RT for 30 minutes. Tothis acrylonitrile (2.6 g, 49.0 mmol) in 15 mL of DMF was added andstirred for 16 hours. Then reaction mixture was poured in water andextracted with ethyl acetate, and concentrated. The crude material waspurified by column chromatography using hexanes: ethyl acetate as eluentto give Intermediate-55 (975 mg).

Synthesis of 4a-methyldecahydroquinoline (Intermediate-56)

A solution of Intermediate-55 (500 mg, 3.0261 mmol) in 25 mL of methanolwas added to 10% of Pd/C (100 mg, 20% W/W) under N₂ atmosphere. N₂ gaswas purged 5 min and then the reaction mixture was kept under hydrogenatmosphere at 60 psi for 16 h. After reaction, the catalyst was filteredand the solvent was concentrated to give Intermediate-56 (287 mg).

Synthesis of Compound (59)

Compound (59) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(59). ¹H NMR (300 MHz, CDCl3): δ 7.70-7.73 (m, 1H), 7.18-7.21 (m, 1H),7.02-7.14 (m, 1H), 7.00-7.02 (m, 1H), 6.75-6.76 (m, 1H), 4.10-4.40 (m,1H), 3.63-3.64 (d, 3H), 2.62-3.00 (m, 5H), 1.64-1.66 (m, 3H), 1.52-1.55(m, 6H), 0.62-1.46 (m, 11H). LC-MS (M+H)⁺=367.3; HPLC purity: 96.39%.

Example 603-(1,4-dimethyl-1H-indol-3-yl)-1-(octahydro-4H-1,4-benzoxazin-4-yl)propan-1-one(60)

Synthesis of Compound (60)

Compound (60) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(60). ¹H NMR (300 MHz, CDCl3): δ 6.99-7.05 (m, 2H), 6.76-6.78 (m, 2H),4.16-4.34 (m, 1H), 3.70-3.88 (m, 1H), 3.63-3.64 (d, 3H), 3.16-3.43 (m,5H), 2.83-2.97 (m, 1H), 2.47-2.73 (m, 4H), 0.90-1.90 (m, 9H). LC-MS(M+H)⁺=341.2; HPLC purity: 98.03%.

Example 613-(1H-indol-3-yl)-1-[(trans-4a,8a)-octahydro-4H-1,4-benzoxazin-4-yl]propan-1-one(61)

Synthesis of 2-chloro-N-[trans-(1,2)-2-hydroxycyclohexyl]acetamide(Intermediate-57)

Starting Material (1 g, 6.6 mmol) was suspended in DCM (10 mL) andtriethylamine (1.94 mL, 13.9 mmol) was added at −10° C. To thischloroacetyl chloride (0.53 mL, 6.6 mmol) was added slowly and themixture was stirred at RT for 16 hours. After reaction was completed thereaction mixture was diluted with saturated aqueous sodium hydrogencarbonate and extracted with 5 percent IPA in ethyl acetate, andconcentrated to give Intermediate-57 (570 mg) as brown oil.

Synthesis of (trans-4a,8a)-hexahydro-2H-1,4-benzoxazin-3(4M-one(Intermediate-58)

To a stirred solution of Intermediate-57 (570 mg, 2.974 mmol) in THF (10mL) at 0° C. under N₂ atmosphere, sodium hydride (60 percent in mineraloil) (131 mg, 3.2714 mmol) was added carefully and the mixture wasstirred for 16 h at room temperature. After completion of the reaction,the reaction mixture was quenched with 1N HCl and extracted with DCM andconcentrated. The crude material was purified by chromatography on asilica gel column chromatography eluting with DCM: MeOH affordedIntermediate-58 (300 mg).

Synthesis of (trans-4a,8a)-octahydro-2H-1,4-benzoxazine(Intermediate-59)

Intermediate-58 (250 mg, 1.6114 mmol) in tetrahydrofuran (10 mL) wasslowly added to a suspension of lithium aluminum hydride (153 mg, 4.0286mmol) at 0° C. Then reaction mixture was refluxed for 16 hours. Aftercompletion of the reaction, the reaction mixture was quenched with 15%sodium hydroxide solution and the insoluble solids were removed byfiltration. The aqueous layer was extracted with diethyl ether. Organiclayers were dried by sodium sulfate and concentrated to giveIntermediate-59 (170 mg) as pale brown oil.

Synthesis of Compound (61)

Compound (61) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(61). ¹H NMR (300 MHz, CDCl3): δ 8.00 (s, 1H), 7.52-7.55 (d, 1H),7.27-7.30 (d, 1H), 7.02-7.14 (m, 2H), 6.95 (s, 1H), 3.67-3.73 (m, 3H),3.32-3.44 (m, 3H), 3.05-3.10 (m, 2H), 2.87-2.90 (m, 1H), 2.45-2.66 (m,4H), 2.15 (s, 1H), 1.81-1.84 (m, 2H), 1.60-1.64 (m, 2H). LC-MS(M+H)⁺=313.2; HPLC purity: 94.77%.

Example 62 3-(1,4-dimethyl-1H-indol-3-yl)-1-[(trans-4a,8a)-octahydro-4H-1,4-benzoxazin-4-yl]propan-1-one(62)

Synthesis of (62)

Compound (62) was synthesized by following the procedure used to make(Scheme 2). The crude product was obtained by evaporating the organiclayer under reduced pressure and was purified by silica gel column usingPetroleum ether: Ethyl acetate as eluent to obtain. ¹H NMR (300 MHz,CDCl3): δ 6.99-7.06 (m, 2H), 6.75-6.77 (d, 2H), 3.68-3.86 (m, 3H), 3.63(s, 3H), 3.35-3.48 (m, 2H), 3.12-3.29 (m, 3H), 2.64 (s, 3H), 2.50-2.61(m, 2H), 1.05-2.14 (m, 8H). LC-MS (M+H)⁺=341.2; HPLC purity: 94.06%.

Example 633-(1-methyl-1H-indol-3-yl)-1-[(trans-4a,8a)-octahydro-4H-1,4-benzoxazin-4-yl]propan-1-one(63)

Synthesis of Compound (63)

Compound (63) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(63). ¹H NMR (300 MHz, CDCl3): δ 7.51-7.53 (d, 1H), 7.12-7.23 (m, 2H),7.01-7.06 (t, 1H), 6.81 (s, 1H), 3.68-3.76 (m, 3H), 3.67 (s, 3H),3.22-3.48 (m, 4H), 3.03-3.08 (t, 2H), 2.51-2.69 (m, 2H), 1.05-2.12 (m,7H). LC-MS (M+H)⁺=327.2; HPLC purity: 96.13%.

Example 643-(4-methyl-1H-indol-3-yl)-1-(octahydro-4H-1,4-benzoxazin-4-yl)propan-1-one(64)

Synthesis of Compound (64)

Compound (64) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(64). ¹H NMR (300 MHz, CDCl3): δ 7.94 (s, 1H), 7.10-7.14 (m, 1H),6.90-7.02 (m, 2H), 6.76-6.80 (t, 1H), 4.11-4.35 (m, 1H), 3.66-3.87 (m,1H), 3.13-3.49 (m, 5H), 2.47-2.99 (m, 6H), 0.91-1.97 (m, 8H). LC-MS(M+H)⁺=327.2; HPLC purity: 98.86%.

Example 653-(1,4-dimethyl-1H-Indol-3-yl)-1-[trans-(4a,8a)-octahydro-4H-1,4-benzoxazin-4-yl]propan-1-one(Peak-1) (65)

Synthesis of Compound (65) (Peak-1)

Mixture of isomers of Compound (60) was separated by reverse phasecolumn chromatography to give Compound (65) (Peak-1). ¹H NMR (300 MHz,CDCl3): δ 6.99-7.06 (m, 2H), 6.75-6.77 (d, 2H), 3.68-3.76 (m, 3H), 3.63(s, 3H), 3.40-3.48 (m, 2H), 3.08-3.35 (m, 3H), 2.64 (s, 3H), 2.45-2.61(m, 2H), 1.05-2.14 (m, 8H). LC-MS (M+H)⁺=341.2; HPLC purity: 97.63% %(column: Zorbax eclipse XDB-C18, RT=15.84 min, mobile phase: 0.01%TFA:MeCN gradient).

Example 663-(1,4-dimethyl-1H-indol-3-yl)-1-[cis-(4a,8a)-octahydro-4H-1,4-benzoxazin-4-yl]propan-1-onePeak-2 (66)

Synthesis of Compound (66) (Peak-2)

Mixture of isomers of Compound (60) was separated by reverse phasecolumn chromatography to give Compound (66) (Peak-2). ¹H NMR (300 MHz,CDCl3): δ 6.98-7.06 (m, 2H), 6.76-6.78 (m, 2H), 4.16-4.34 (m, 1H),3.69-3.87 (m, 1H), 3.63 (d, 3H), 3.07-3.43 (m, 5H), 2.81-2.97 (m, 1H),2.43-2.73 (m, 5H), 0.91-1.94 (m, 8H). LC-MS (M+H)⁺=341.2; HPLC purity:96.84% (column: Zorbax eclipse XDB-C18, RT=16.19 min, mobile phase:0.01% TFA:MeCN gradient).

Example 673-(1H-indol-3-yl)-1-(octahydro-4H-1,4-benzoxazin-4-yl)propan-1-one (67)

Synthesis of Compound (67)

Compound (67) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(66). ¹H NMR (300 MHz, CDCl3): δ 8.02 (s, 1H), 7.53-7.56 (m, 1H),7.27-7.30 (m, 1H), 7.02-7.15 (m, 2H), 6.96 (s, 1H), 4.13-4.32 (m, 1H),3.61-3.84 (m, 1H), 3.03-3.47 (m, 5H), 2.47-2.93 (m, 3H), 0.94-2.12 (m,8). LC-MS (M+H)⁺=313.2; HPLC purity: 98.01%.

Example 681-(2,2-dimethyloctahydro-4H-1,4-benzoxazin-4-yl)-3-(4-methyl-1H-indol-3-yl)propan-1-one(68)

Synthesis of 2-bromo-N-(2-hydroxyphenyl)-2-methylpropanamide(Intermediate-60)

Intermediate-60 was synthesized by following the procedure used to makeIntermediate-57 (Scheme 38).

Synthesis of 2,2-dimethyl-2H-1,4-benzoxazin-3(4H)-one (Intermediate-61)

Intermediate-61 was synthesized by following the procedure used to makeIntermediate-58 (Scheme 38).

Synthesis of 2,2-dimethyl-3,4-dihydro-2H-1,4-benzoxazine(Intermediate-62)

Intermediate-62 was synthesized by following the procedure used to makeIntermediate-29 (Scheme 22).

Synthesis of 2,2-dimethyloctahydro-2H-1,4-benzoxazine (Intermediate-63)

Intermediate-63 was synthesized by following the procedure used to makeIntermediate-30 (Scheme 22).

Synthesis of Compound (68)

Compound (68) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(68). ¹H NMR (300 MHz, CDCl3): δ 7.93 (s, 1H), 7.10-7.13 (d, 1H),6.91-7.02 (m, 2H), 6.76-6.81 (m, 1H), 4.04-4.40 (m, 1H), 3.39-3.80 (m,1H), 2.96-3.31 (m, 4H), 2.51-2.81 (m, 6H), 1.65-1.93 (m, 3H), 1.04-1.41(m, 10H). LC-MS=355.22; HPLC purity: 94.97%.

Example 693-(1,4-dimethyl-1H-indol-3-yl)-1-(2-methyloctahydro-4H-1,4-benzoxazin-4-yl)propan-1-one(69)

Synthesis of Intermediate-64 (2-methyloctahydro-2H-1,4-benzoxazine)

Intermediate-64 was synthesized by following the procedure used to makeIntermediate-63 (Scheme 39).

Synthesis of Compound (69)

Compound (69) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(69). ¹H NMR (300 MHz, CDCl3): δ 6.99-7.06 (m, 2H), 6.77-6.77 (d, 2H),3.86-4.31 (m, 1H), 3.63 (s, 3H), 3.29-3.44 (m, 2H), 3.16-3.13 (m, 3H),3.04-3.12 (m, 1H), 2.68-2.75 (m, 1H), 2.64 (s, 3H), 2.42-2.61 (m, 2H),1.80-2.24 (m, 1H), 1.63-1.76 (m, 3H), 1.29-1.43 (m, 2H), 1.11-1.13 (d,1H), 1.01-1.07 (m, 2H), 0.92-0.98 (m, 1H). LC-MS (M+H)⁺=355.2; HPLCpurity: 95.0%.

Example 703-(1,4-dimethyl-1H-indol-3-yl)-1-(2,2-dimethyloctahydro-4H-1,4-benzoxazin-4-yl)propan-1-one(70)

Synthesis of Compound (70)

Compound (70) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(70). ¹H NMR (300 MHz, CDCl3): δ 6.99-7.06 (m, 2H), 6.76-6.78 (m, 2H),4.03-4.39 (m, 1H), 3.62-3.63 (d, 3H), 3.41 (m, 1H), 2.95-3.29 (m, 4H),2.47-2.80 (m, 5H), 0.99-1.93 (m, 14H). LC-MS (M+H)⁺=369.2; HPLC purity:98.90%.

Example 713-methyl-3-(1-methyl-1H-indol-3-yl)-1-(octahydro-4H-1,4-benzoxazin-4-yl)butan-1-one(71)

Synthesis of Compound (71)

Compound (71) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(71). ¹H NMR (300 MHz, CDCl3) δ 7.70-7.79 (m, 1H), 7.35-7.40 (t, 1H),7.03-7.11 (m, 3H), 4.04-4.11 (m, 1H), 3.70 (m, 3H), 3.50 (m, 3H),2.00-3.40 (m, 5H), 0.83-1.70 (m, 14H). LC-MS (M+H)⁺=355.3; HPLC purity:88.82%.

Example 723-(4-fluoro-1H-indol-3-yl)-1-(octahydro-4H-1,4-benzoxazin-4-yl)propan-1-one(72)

Synthesis of 3-(4-fluoro-1H-indol-3-yl)propanoic acid (Intermediate-65)

Intermediate-65 was synthesized by following the procedure used to makeIntermediate-28 (Scheme 21).

Synthesis of Compound (72)

Compound (72) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(72). ¹H NMR (300 MHz, CDCl3): 8.12 (s, 1H), 6.99-7.08 (m, 2H), 6.95 (s,1H), 6.64-6.74 (m, 1H), 4.15-4.20 (m, 1H), 3.66-3.85 (m, 1H), 3.12-3.43(m, 4H), 2.65-2.97 (m, 3H), 1.18-2.10 (m, 9H). LC-MS (M+H)⁺=331.2; HPLCpurity: 97.15%.

Example 732-(1,3-benzothiazol-2-ylsulfanyl)-1-(octahydroquinolin-1(2H)-yl)ethanone(73)

Synthesis of ethyl (1,3-benzothiazol-2-ylsulfanyl)acetate(Intermediate-66)

To a 100 mL RB flask fitted with magnetic stirrer was charged 10 mL ofdimethylformamide. To this Starting Material-25 (1.0 g, 5.979 mmol)followed by potassium carbonate (2.477 g, 17.925 mmol) were added andstirred at room temperature for 30 minutes. Then ethylbromoacetate(1.997 g, 11.958 mmol) was added. The resulting solution was stirred atroom temperature for 15 hours. After completion of the reaction(reaction monitored by TLC), the reaction mixture was concentrated. Theresulting crude was taken in ethyl acetate (100 mL) and washed withwater (100 mL×3), brine (100 mL) and concentrated to giveIntermediate-66 (2.6 g).

Synthesis of (1,3-benzothiazol-2-ylsulfanyl)acetic acid(Intermediate-67)

To a 100 mL RB flask fitted with magnetic stirrer was charged 15 mL oftetrahydrofuran, 0.5 mL water, 0.5 mL methanol. To this Intermediate-66(2.6 g, 10.262 mmol), followed by lithium hydroxide (738.9 mg, 30.788mmol) were added at 0° C. Then the reaction mixture was stirred at roomtemperature for 7 hours. After completion of the reaction (reactionmonitored by TLC), reaction mass was diluted with 10 mL of water andwashed with 20 mL dichloro methane DCM (2×10 mL). Then aqueous layer wasacidified with 1N HCl (pH=2), and the resulted solids were filtered anddried to give Intermediate-67 (1.17 g).

Synthesis of Compound (73)

Compound (73) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(73). ¹H NMR (300 MHz, CDCl3): δ 7.69-7.73 (m, 1H), 7.58-7.60 (d, 1H),7.21-7.28 (m, 1H), 7.11-7.16 (t, 1H), 4.33-4.40 (m, 1H), 4.19-4.29 (m,2H), 3.78-3.82 (m, 1H), 2.47-3.05 (m, 1H), 1.56-1.77 (m, 5H), 1.42 (s,2H), 1.14-1.33 (m, 6H). LC-MS (M+H)⁺=347.1; HPLC purity: 97.01%.

Example 742-(1,3-benzothiazol-2-ylsulfanyl)-2-methyl-1-(octahydroquinolin-1(2H)-yl)propan-1-one(74)

Synthesis of 2-(1,3-benzothiazol-2-ylsulfanyl)-2-methylpropanoic acid(Intermediate-68)

Intermediate-68 was synthesized by following the procedure used to makeIntermediate-67 (Scheme 42).

Synthesis of Compound (74)

Compound (74) was synthesized by following the procedure used to make 1)(Scheme 2). The crude product was obtained by evaporating the organiclayer under reduced pressure and was purified by silica gel column usingPetroleum ether: Ethyl acetate as eluent to obtain Compound (77). ¹H NMR(300 MHz, CDCl3): δ 7.86-7.89 (d, 1H), 7.68-7.71 (m, 1H), 7.33-7.38 (m,1H), 7.23-7.29 (m, 1H), 4.58-4.62 (m, 2H), 2.69-3.05 (m, 1H), 1.63-1.72(m, 12H), 1.42-1.45 (m, 1H), 1.22-1.40 (m, 6H). LC-MS (M+H)⁺=375.1; HPLCpurity: 91.48%.

Example 753-(1,3-benzothiazol-2-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one(75)

Synthesis of 3-(1,3-benzothiazol-2-yl)propanoic acid (Intermediate-69)

Starting material-27 (3.97 mmol) in benzene was added drop wise to thesolution of Starting Material-26 (3.97 mmol) in benzene. The resultingsolution was heated to reflux for 2 hours. After 2 hours the reactionmass was cooled to room temperature and extracted with 10% sodiumhydroxide solution. The aqueous layer was acidified using Conc.HCl (3ml) at 0° C. The resulting solids were filtered and dried at roomtemperature to get Intermediate-69 (660 mg).

Synthesis of Compound (75)

Compound (75) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(75). ¹H NMR (300 MHz, CDCl3): δ 7.93-7.97 (m, 1H), 7.81-7.84 (d, 1H),7.41-7.46 (m, 1H), 7.31-7.36 (m, 1H), 4.49-4.67 (m, 1H), 3.65-3.83 (m,1H), 3.44-3.51 (m, 2H), 2.61-3.10 (m, 3H), 1.71-1.78 (m, 6H), 1.30-1.42(m, 7H). LC-MS (M+H)⁺=329.1; HPLC purity: 98.13%.

Example 76 3-(1,3-benzothiazol-2-yl)-1-(2-methyloctahydroquinolin-1(2H)-yl)propan-1-one (76)

Synthesis of Compound (76)

Compound (76) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(76). ¹H NMR (300 MHz, CDCl3): δ 7.86-7.89 (d, 1H), 7.75-7.77 (d, 1H),7.34-7.39 (t, 1H), 7.24-7.29 (t, 1H), 4.45-4.70 (m, 1H), 3.67-4.08 (m,1H), 3.40-3.45 (t, 2H), 2.94-3.05 (m, 1H), 2.77-2.85 (m, 1H), 1.58-1.76(m, 9H), 1.20-1.23 (d, 7H). LC-MS (M+H)⁺=343.1; HPLC purity: 95.24%.

Example 77 methyl1-[3-(1,3-benzothiazol-2-yl)propanoyl]decahydroquinoline-4-carboxylate(80)

Synthesis of Compound (77)

Compound (77) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(77). ¹H NMR (300 MHz, CDCl3): δ 7.86-7.89 (d, 1H), 7.75-7.77 (d, 1H),7.35-7.39 (t, 1H), 7.25-7.30 (t, 1H), 3.86-4.32 (m, 1H), 3.61 (d, 3H),3.39-3.44 (t, 2H), 2.55-3.01 (m, 2H), 0.90-2.24 (m, 14H). LC-MS(M+H)⁺=387.2; HPLC purity: 95.28%.

Example 783-(1,3-benzothiazol-2-yl)-1-(4a-methyloctahydroquinolin-1(2H)-yl)propan-1-one(78)

Synthesis of Compound (78)

Compound (78) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(78). ¹H NMR (300 MHz, CDCl3): δ 7.85-7.89 (m, 1H), 7.74-7.77 (d, 1H),7.34-7.39 (t, 1H), 7.24-7.29 (t, 1H), 4.23-4.50 (m, 1H), 3.31-3.64 (m,3H), 2.54-3.09 (m, 3H), 0.84-1.96 (m, 15H). LC-MS (M+H)⁺=343.2; HPLCpurity: 97.13%.

Example 793-(1,3-benzothiazol-2-yl)-1-[trans-(4a,8a)-octahydro-4H-1,4-benzoxazin-4-yl]propan-1-one(79)

Synthesis of Compound (79)

Compound (79) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(79). ¹H NMR (300 MHz, CDCl3): δ 7.86-7.89 (d, 1H), 7.75-7.77 (d, 1H),7.35-7.39 (t, 1H), 7.25-7.30 (t, 1H), 3.80-3.93 (m, 2H), 3.39-3.55 (m,5H), 2.78-2.96 (m, 2H), 1.18-2.22 (m, 9H). LC-MS (M+H)⁺=331.22; HPLCpurity: 96.52%.

Example 803-(1,3-benzothiazol-2-yl)-1-(octahydro-4H-1,4-benzoxazin-4-yl)propan-1-one(80)

Synthesis of Compound (80)

Compound (80) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(80). ¹H NMR (300 MHz, CDCl3): δ 7.85-7.89 (m, 1H), 7.75-7.77 (d, 1H),7.34-7.40 (m, 1H), 7.25-7.30 (m, 1H), 4.11-4.31 (m, 1H), 3.80-3.91 (m,1H), 3.31-3.57 (m, 5H), 2.68-3.04 (m, 2H), 1.66-2.24 (m, 6H), 1.32-1.44(m, 3H). LC-MS (M+H)⁺=331.2; HPLC purity: 94.03%.

Example 813-(1,3-benzothiazol-2-yl)-1-(octahydro-1H-indol-1-yl)propan-1-one (81)

Synthesis of Compound (81)

Compound (81) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(81). ¹H NMR (300 MHz, CDCl3): δ 7.89-7.91 (d, 1H), 7.75-7.77 (d, 1H),7.36-7.41 (t, 1H), 7.26-7.31 (t, 1H), 3.64-4.03 (m, 1H), 3.32-3.52 (m,3H), 2.71-2.97 (m, 2H), 0.95-2.24 (m, 12H). LC-MS (M+H)⁺=315.1; HPLCpurity: 95.99%.

Example 823-(1,3-benzothiazol-2-yl)-1-(octahydro-2H-isoindol-2-yl)propan-1-one(82)

Synthesis of Compound (82)

Compound (82) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(82). ¹H NMR (300 MHz, CDCl3): δ 7.91-7.94 (d, 1H), 7.75-718 (d, 1H),7.37-7.42 (t, 1H), 7.27-7.32 (t, 1H), 3.22-3.47 (m, 6H), 2.81-2.91 (m,2H), 2.10-2.21 (m, 2H), 1.89 (s, 1H), 1.30-1.40 (m, 7H). LC-MS(M+H)⁺=315.2; HPLC purity: 98.47%.

Example 833-(1,3-benzothiazol-2-yl)-1-(2-methyloctahydro-1H-indol-1-yl)propan-1-one(83)

Synthesis of Compound (83)

Compound (83) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(83). ¹H NMR (300 MHz, CDCl3): δ 7.87-7.90 (d, 1H), 7.75-7.77 (d, 1H),7.35-7.40 (t, 1H), 7.25-7.30 (t, 1H), 3.86-4.13 (m, 1H), 3.62-3.69 (m,1H), 3.34-3.52 (m, 2H), 2.68-2.97 (m, 2H), 1.80-2.14 (m, 4H), 1.00-1.67(m, 10H). LC-MS (M+H)⁺=329.2; HPLC purity: 97.23%.

Example 841-(octahydroquinolin-1(2H)-yl)-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propan-1-one(84)

Synthesis of 3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propanoic acid(Intermediate-70)

Intermediate-70 was synthesized by following the procedure used to makeIntermediate-9 (Scheme 4).

Synthesis of Compound (84)

Compound (84) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(84). ¹H NMR (300 MHz, CDCl3): δ 9.77-9.80 (d, 1H), 8.29-8.30 (d, 1H),7.93-7.96 (m, 1H), 7.16-7.18 (d, 1H), 7.05-7.11 (m, 1H), 4.50-4.68 (m,1H), 3.57-3.65 (m, 1H), 3.07-3.15 (m, 2H), 2.56-2.95 (m, 4H), 1.25-1.87(m, 12H). LC-MS (M+H)⁺=312.3; HPLC purity: 95.95%.

Example 851-(octahydroquinolin-1(2H)-yl)-3-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]propan-1-one(85)

Synthesis of Compound (85)

Compound (85) was synthesized by following the procedure used to make(51) (Scheme 34). The crude product was obtained by evaporating theorganic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(85). ¹H NMR (300 MHz, CDCl3): δ 8.34-8.36 (t, 1H), 8.09-8.13 (t, 2H),7.78-7.81 (d, 1H), 7.37-7.49 (m, 4H), 7.08-7.14 (m, 1H), 4.42-4.59 (m,1H), 3.48-3.60 (m, 1H), 2.89-2.97 (m, 2H), 2.47-2.75 (m, 3H), 1.25-1.74(m, 13H). LC-MS (M+H)⁺=452.2; HPLC purity: 99.87%.

Example 861-(2-methyloctahydroquinolin-1(2H)-yl)-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propan-1-one(86)

Synthesis of Compound (86)

Compound (86) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(86). ¹H NMR (300 MHz, CDCl3): δ 9.48 (s, 1H), 8.21-8.23 (d, 1H),7.86-7.90 (m, 1H), 6.98-7.09 (m, 2H), 4.46-4.70 (m, 1H), 3.47-3.90 (m,1H), 3.03-3.08 (m, 2H), 2.49-2.77 (m, 2H), 1.07-1.86 (m, 16H). LC-MS(M+H)⁺=326.2; HPLC purity: 97.13%.

Example 873-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one (87)

Synthesis of Compound (87)

Compound (87) was synthesized by following the procedure used to makeCompound (27) (Scheme 26). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(87). ¹H NMR (300 MHz, CDCl3): δ 8.25 (s, 1H), 7.82-7.84 (m, 1H),6.94-7.00 (m, 2H), 4.43-4.61 (m, 1H), 3.77 (s, 1H), 3.38-3.62 (m, 1H),2.98-3.05 (m, 2H), 2.45-2.92 (m, 4H), 1.18-1.66 (m, 14H). LC-MS(M+H)⁺=326.3; HPLC purity: 98.68%.

Example 883-(1H-indazol-3-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one (88)

Synthesis of 3-iodo-1H-indazole (Intermediate-71)

Starting Material-28 (42 mmol) in DMF (50 ml) was cooled to 0° C. Thenpotassium hydroxide (84.6 mmol) was added which was followed by theaddition of Iodine (42 mmol). The reaction mixture was maintained atroom temperature for 2 hours. Then the reaction mixture was diluted withice cooled water and extracted with ethyl acetate. The organic layer wasdried over anhydrous MgSO4, and evaporated to give Intermediate-71 (8 g,pale yellow solid).

Synthesis of tert-butyl 3-iodo-1H-indazole-1-carboxylate(Intermediate-72)

DMAP (16.37 mmol) was added to Intermediate-71(39 mmol) in acetonitrile(50 ml). The reaction mixture was then cooled to 0° C. BOC anhydride(39.9 mmol) was added to the cooled reaction mixture. The reaction wascarried out at room temperature for 16 hours. Then the reaction mixturewas diluted with water (100 ml) and extracted with ethyl acetate. Theorganic layer was dried over anhydrous Na₂SO₄ and evaporated to obtainIntermediate-72 (7 g, pale yellow solid).

Synthesis of tert-butyl3-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-1H-indazole-1-carboxylate(Intermediate-73)

To Triethylamine (3 ml), Intermediate-72 (5.8 mmol) was added to whichmethyl acrylate (5.8 mmol) was further added. The reaction mixture waspurged with argon for 10 minutes. The Pd (II) acetate (0.5 mmol) andtri-o-tolyl phosphine (0.5 mmol) was added to the reaction mixture. Thereaction was carried out for 16 hours at room temperature. Then thereaction mixture was filtered through celite, the filtrate was dilutedwith ethyl acetate (250 ml) and washed with NaHCO₃ (50 ml) and brinesolution. The organic layer was dried over anhydrous MgSO₄, and obtainedthe crude product by evaporating the organic layer under reducedpressure. The crude product was purified using silica gel column usingHexane and Ethyl acetate as the eluent, to obtain Intermediate-73 (500mg, pale yellow liquid). ¹H NMR (300 MHz, DMSO-d₆): δ 8.24-8.27 (d, 1H),8.13-8.16 (d, 1H), 7.85-7.90 (d, 1H), 7.65-7.71 (t, 1H), 7.45-7.50 (t,1H), 6.96-7.02 (d, 1H), 3.80 (s, 3H), 1.67 (s, 9H).

Synthesis of tert-butyl3-(3-ethoxy-3-oxopropyl)-1H-indazole-1-carboxylate (Intermediate-74)

Intermediate-73 (1.58 mmol) dissolved in EtOAc (10 ml) was taken in apar shaker flask. To this reaction mixture 10% Pd—C (20% W/W) was added.The resulting reaction mixture was stirred under hydrogen atmosphere (50psi) for 5 hours at room temperature. After 5 hours the reaction mixturewas filtered through celite. The filtrate was further concentrated togive Intermediate-74 (200 mg, pale yellow liquid). ¹H NMR (300 MHz,DMSO-d₆): δ 7.99-8.02 (d, 1H), 7.62-7.65 (d, 1H), 7.44-7.47 (t, 1H),7.21-7.26 (t, 1H), 3.63 (s, 3H), 3.21-3.26 (t, 2H), 2.84-2.89 (t, 2H),1.65 (s, 9H).

Synthesis of 3-(1H-indazol-3-yl) propanoic acid (Intermediate-75)

Intermediate 74 (0.6 mmol) is added to a solvent (equal ratio of thesolvents THF (2 ml) and MeOH (2 ml)) to which LION (3.4 mmol) solutionin 1 ml water is further added. The reaction was allowed for 16 hours atroom temperature. After 16 hours the reaction mixture was concentrated,and acidified with 1N HCl (pH=2). The reaction mixture was thenextracted with ethyl acetate. The organic layer was dried over anhydrousMgSO₄, and evaporated to obtain Intermediate-75(100 mg, pale yellowliquid).

Synthesis of Compound (88)

Compound (88) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(88). ¹H NMR (300 MHz, CDCl3): δ 7.72-7.74 (d, 1H), 7.36-7.47 (m, 2H),7.11-7.16 (m, 1H), 4.42-4.61 (m, 1H), 3.57-3.74 (m, 1H), 3.10-3.35 (m,3H), 2.22-3.00 (m, 3H), 1.56-1.67 (m, 12H). LC-MS (M+H)⁺=312.2; HPLCpurity: 90.23%.

Example 893-(1-methyl-1H-indazol-3-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one(89)

Synthesis of ethyl 3-(1H-indazol-3-yl)propanoate (Intermediate-76)

Intermediate-74 (1.7 mmol) in DCM (5 ml) was cooled to 0° C., followedby the addition of TFA (5.1 mmol). The reaction was allowed for 3 hoursat room temperature. After 3 hours the reaction mixture was concentratedand diluted with ethyl acetate (50 ml). Further washed with NaHCO₃solution (20 ml), the organic layer was dried over anhydrous MgSO₄, andevaporated to obtain Intermediate-76 (250 mg, pale yellow liquid).

Synthesis of 3-(1-methyl-1H-Indazol-3-yl)propanoic acid(Intermediate-77)

Intermediate-76 (1.2 mmol) was added to dry THF (5 ml) and was cooled to0° C. Then to the reaction mixture, NaH (2.4 mmol) was added. After 15minutes, Mel (1.8 mmol) was added to the reaction mixture. The reactionwas allowed for 3 hours at room temperature. After 3 hours the reactionmixture was quenched with 1N HCl and extracted with ethyl acetate. Theorganic layer was dried over anhydrous MgSO₄, and evaporated to obtainIntermediate-77 (100 mg, pale yellow liquid).

Synthesis of Compound (89)

Compound (89) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(89). ¹H NMR (300 MHz, CDCl3): δ 7.64-7.67 (d, 1H), 7.24-7.33 (m, 2H),7.03-7.11 (m, 1H), 4.44-4.62 (m, 1H), 3.93-3.95 (d, 3H), 3.57-3.70 (m,1H), 3.21-3.26 (m, 2H), 2.42-2.93 (m, 3H), 1.21-1.68 (m, 13H). LC-MS(M+H)⁺=326.3; HPLC purity: 96.80%.

Example 903-(1H-benzotriazol-1-yl)-1-(4a-methyloctahydroquinolin-1(2H)-yl)propan-1-one(90)

Synthesis of ethyl 3-(1H-benzotriazol-1-yl)propanoate (Intermediate-78)

The starting material-29 (4.1 mmol) in dry THF (5 ml) was cooled to 0°C., followed by the addition of NaH (6.0 mmol). The reaction mixture wasgradually warmed to room temperature and allowed to react for 20minutes. The reaction mixture was again cooled to 0° C., followed by thedrop wise addition of ethyl 3-bromopropanoate (4.6 mmol) in THF (2.5ml). The reaction was allowed for 12 hours at room temperature. After 12hours the reaction mixture was quenched with ice cooled water andextracted with ethyl acetate. The organic layer was dried over anhydrousMgSO₄, and concentrated to obtain Intermediate-78 (70 mg). 1H NMR (300MHz, CDCl3): δ 7.98-8.01 (1H, d), 7.55-7.58 (d, 1H), 7.41-7.46 (t, 1H),7.28-7.33 (t, 1H), 4.82-4.87 (t, 2H), 4.00-4.07 (t, 2H), 3.00-3.05 (t,2H), 1.08-1.1 (t, 3H).

Synthesis of 3-(1H-benzotriazol-1-yl)propanoic acid (Intermediate-79)

At 0° C., LiOH (1.5 mmol) in water (1 ml) was added to Intermediate-78in the solvent THF: MeOH (1:1, 3 ml each). The reaction was allowed for12 hours at room temperature. After 12 hours the reaction mixture wasconcentrated, further acidified with 1N HCl (pH=2). The reaction mixturewas extracted with ethyl acetate. The organic layer was dried overanhydrous MgSO₄, and evaporated under reduced pressure to obtainIntermediate-79 (60 mg). 1H NMR (300 MHz, CDCl3): δ 7.29-8.00 (4H, m),4.82-4.87 (t, 2H), 3.09-3.14 (t, 2H).

Synthesis of Compound (90)

Compound (90) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(90). ¹H NMR (300 MHz, CDCl3): δ 7.96-7.99 (m, 1H), 7.60-7.62 (m, 1H),7.42-7.47 (m, 1H), 7.28-7.33 (m, 1H), 4.88-4.94 (m, 2H), 4.10-4.50 (m,1H), 3.20-3.30 (m, 1H), 2.40-3.20 (m, 3H), 0.70-1.94 (m, 15H). LC-MS(M+H)⁺=327.2; HPLC purity: 99.10%.

Example 913-(1H-benzotriazol-1-yl)-1-(octahydro-4H-1,4-benzoxazin-4-yl)propan-1-one(91)

Synthesis of Compound (91)

Compound (91) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(91). ¹H NMR (300 MHz, CDCl3): δ 7.96-7.99 (m, 1H), 7.57-7.61 (m, 1H),7.41-7.46 (t, 1H), 7.27-7.33 (t, 1H), 4.89-4.94 (m, 2H), 3.77-4.11 (m,2H), 2.90-3.31 (m, 5H), 1.18-1.88 (m, 9H). LC-MS (M+H)⁺=315.2; HPLCpurity: 92.32%.

Example 923-(5-fluoro-1H-indol-3-yl)-1-(2-methyloctahydroquinolin-1(2H)-yl)butan-1-one(92)

Synthesis of Compound (92)

Compound (92) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(92). ¹H NMR (300 MHz, CDCl3): δ 8.00 (s, 1H), 7.29 (m, 2H), 6.98 (s,1H), 6.82 (t, 1H), 4.40-4.70 (m, 1H), 2.61-3.58 (m, 5H), 1.59 (m, 9H),1.35-1.43 (t, 6H), 1.02 (m, 3H). LC-MS (M+H)⁺=357.2; HPLC purity:82.80%.

Example 93 3-(1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)propan-1-one(93)

Synthesis of Compound (93)

Compound (93) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(93). ¹H NMR (300 MHz, DMSO-d6): δ 10.75 (s, 1H), 7.48-7.52 (t, 1H),7.30-7.33 (m, 1H), 7.12 (s, 1H), 6.93-7.07 (m, 2H), 4.29-4.48 (m, 1H),3.60-3.71 (m, 1H), 2.43-2.96 (m, 5H), 1.23-1.70 (m, 13H). LC-MS(M+H)⁺=311.1; HPLC purity: 97.67%.

Example 943-(1-methyl-1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)butan-1-one(94)

Synthesis of Compound (94)

Compound (94) was synthesized by following the procedure used to makeCompound (27) (Scheme 26). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(94). ¹H NMR (300 MHz, CDCl3): δ 7.57 (m, 1H), 7.10-7.28 (m, 2H),6.98-7.03 (m, 1H), 6.78-6.80 (d, 1H), 4.43-4.60 (m, 1H), 3.65 (m, 3H),3.51-3.59 (m, 2H), 2.37-2.87 (m, 3H), 0.90-1.63 (m, 16H). LC-MS(M+H)⁺=339.2; HPLC purity: 91.90%.

Example 953-(1H-indol-3-yl)-4-methyl-1-(octahydroquinolin-1(2H)-yl)pentan-1-one(95)

Synthesis of Compound (95)

Compound (95) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(95). ¹H NMR (300 MHz, CDCl3): δ 8.51-8.55 (d, 1H), 7.53-7.61 (m, 1H),7.22-7.25 (d, 1H), 6.94-7.06 (m, 2H), 6.84 (d, 1H), 4.32-4.47 (m, 1H),3.35-3.65 (m, 1H), 3.02-3.20 (m, 1H), 2.28-2.92 (m, 3H), 0.78-1.99 (m,20H). LC-MS (M+H)⁺=353.3; HPLC purity: 88.81%.

Example 96N-[3-(1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)-1-oxopropan-2-yl]acetamide(96)

Synthesis of Compound (96)

Compound (96) was synthesized by following the procedure used to makeCompound (1) (Scheme 1). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(96). ¹H NMR (300 MHz, DMSO-d6): δ 10.78-10.85 (m, 1H), 8.19-8.22 (m,1H), 7.52-7.58 (m, 1H), 7.30-7.33 (m, 1H), 6.97-7.11 (m, 3H), 5.06 (m,1H), 4.20 (m, 1H), 2.86-3.07 (m, 3H), 0.96-1.83 (m, 17H). LC-MS(M+H)⁺=368.1; HPLC purity: 94.46%.

Example 97[2-(1-methyl-1H-indol-3-yl)cyclopropyl](octahydroquinolin-1(2H)-yl)methanone(97)

Synthesis of 1-benzyl-1H-indole-3-carbaldehyde (Intermediate-80)

To a 250 ml 3 neck RBF was charged 40 ml of THF. To the stirred solutionNaH (1.24 g, 31.0 mmol) was added followed by addition of StartingMaterial-30 (3 g, 20.6 mmol). The reaction mixture was stirred at RT for30 min. Then benzyl bromide (2.7 ml, 22.6 mmol) was added to the mixtureat 0° C. Resulted reaction mixture was stirred at RT for 12 h. Aftercompletion of reaction, the reaction mixture was quenched with ice andextracted with ethylacetate and concentrated. Crude Material waspurified by silica gel column chromatography eluting with hexanes: EtOActo give Intermediate-80 (4.25 g).

Synthesis of ethyl (2E)-3-(1-benzyl-1H-indol-3-yl)prop-2-enoate(Intermediate-81)

Intermediate-81 was synthesized by following the procedure used to makeIntermediate-7 (Scheme 4). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtainIntermediate-81 (3.85 g)

Synthesis of ethyl 2-(1-benzyl-1H-Indol-3-yl)cyclopropanecarboxylateIntermediate-82)

To a 250 ml 3neck RB was charged 40 ml of DMSO. To this Intermediate-81(3.5 g, 11.4 mmol), TMSOI (2.7 g, 12.6 mmol), and then KOH (55 mg, 0.98mmol) was added. Resulting reaction mixture was stirred at RT for 12hours. After reaction was completed (monitored by TLC) the reactionmixture was quenched with water and extracted with ethyl acetate, andconcentrated. Crude material was purified by silica gel columnchromatography eluting with hexanes: EtOAc to give Intermediate-82 (655mg).

Synthesis of 2-(1-benzyl-1H-indol-3-yl)cyclopropanecarboxylic acid(Intermediate-83)

Intermediate-83 was synthesized by following the procedure used to makeIntermediate-79 (Scheme 49).

Synthesis of [2-(1-benzyl-1H-indol-3-yl)cyclopropyl] (octahydroquinolin-1(2H)-yl)methanone (Intermediate-84)

Intermediate-84 was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtainIntermediate-84 (275 mg).

Synthesis of [2-(1H-indol-3-yl)cyclopropyl](octahydroquinolin-1(2H)-yl)methanone (Intermediate-85)

5 ml of DMSO was taken in a 25 ml single neck RB. To thisIntermediate-84 (275 mg, 0.66 mmol) followed by potassium-t-butoxide(525 mg, 4.66 mmol) in THF was added and stirred at rt for 3 hours.After reaction quenched with NH4Cl solution and extracted with ethylacetate. The combined organic layers were washed with DM water and brinesolution and concentrated. The crude product was obtained purified bysilica gel column using Petroleum ether: Ethyl acetate as eluent toobtain Intermediate-85 (18 mg).

Synthesis of Compound (97)

Compound (97) was synthesized by following the procedure used to makeIntermediate-77 (Scheme 48). The crude product was obtained byevaporating the organic layer under reduced pressure and was purified bysilica gel column using Petroleum ether: Ethyl acetate as eluent toobtain Compound (97). ¹H NMR (300 MHz, CDCl3): δ 7.52-7.58 (m, 1H),7.13-7.22 (m, 2H), 7.01-7.06 (m, 1H), 6.65-6.78 (m, 1H), 4.41-4.66 (m,1H), 3.84-4.06 (m, 1H), 3.70 (s, 3H), 2.98-3.33 (m, 1H), 2.42-2.76 (m,2H), 1.52-1.86 (m, 9H), 1.26-1.45 (m, 6H). LC-MS (M+H)⁺=337.2; HPLCpurity: 96.48%.

Example 982-(1H-indol-3-ylmethyl)-3-(octahydroquinolin-1(2H)-yl)-3-oxopropanenitrile(98)

Synthesis of Compound (98)

Compound (98) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(98). ¹H NMR (300 MHz, CDCl3): δ 8.11 (s, 1H), 7.48-7.55 (m, 1H),7.31-7.34 (d, 1H), 7.09-7.13 (m, 3H), 4.36-4.59 (m, 1H), 3.82-4.03 (m,1H), 3.26-3.48 (m, 3H), 2.51-2.85 (m, 1H), 2.15-2.30 (m, 1H), 1.93-2.01(m, 1H), 1.52-1.64 (m, 11H). LC-MS (M+H)⁺=336.2; HPLC purity: 92.84%.

Example 99 2-(1H-indol-3-yloxy)-1-(octahydroquinolin-1(2H)-yl)ethanone(99)

Synthesis of Compound (99)

Compound (99) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(99). ¹H NMR (300 MHz, CDCl3): δ 7.53-7.58 (t, 1H), 7.50 (s, 1H),7.20-7.23 (d, 1H), 7.09-7.14 (t, 1H), 6.98-7.03 (t, 1H), 6.76-6.77 (t,1H), 4.57-4.72 (m, 2H), 4.35-4.52 (m, 1H), 3.82-4.02 (m, 1H), 2.54-3.07(m, 1H), 1.26-1.78 (m, 13H). LC-MS (M+H)⁺=313.2; HPLC purity: 96.80%.

Example 1002-[(1-methyl-1H-indol-3-yl)oxy]-1-(octahydroquinolin-1(2H)-yl)propan-1-one(100)

Synthesis of Compound (100)

Compound (100) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(100). ¹H NMR (300 MHz, CDCl3): δ 7.53-7.55 (m, 1H), 7.14-7.18 (m, 2H),6.97-6.99 (m, 1H), 6.53-6.55 (t, 1H), 4.71-4.79 (m, 1H), 4.08-4.58 (m,2H), 3.58 (d, 3H), 2.47-2.95 (m, 1H), 1.18-1.68 (m, 16H). LC-MS(M+H)⁺=341.2; HPLC purity: 98.96%.

Example 101 methyl1-[3-(1H-indol-3-yl)-4-methylpentanoyl]decahydroquinoline-4-carboxylate(101)

Synthesis of Compound (101)

Compound (101) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(101). ¹H NMR (300 MHz, CDCl3): δ 8.02 (s, 1H), 7.56-7.59 (d, 1H),7.23-7.26 (m, 1H), 7.06-7.11 (t, 1H), 6.97-7.04 (t, 1H), 6.91-6.92 (d,1H), 4.00-4.09 (m, 1H), 3.66-3.67 (d, 1H), 3.56 (s, 3H), 3.45-3.49 (d,1H), 3.17-3.24 (m, 1H), 2.66-2.81 (m, 2H), 2.24-2.28 (m, 1H), 1.97-2.15(m, 1H), 1.07-1.78 (m, 11H), 0.93-0.96 (d, 3H), 0.77-0.80 (d, 3H). LC-MS(M+H)⁺=411.3; HPLC purity: 94.17%.

Example 102 methyl1-[3-(1H-indol-3-yl)butanoyl]decahydroquinoline-4-carboxylate (102)

Synthesis of Compound (102)

Compound (102) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(102). ¹H NMR (300 MHz, CDCl3): δ 7.99 (s, 1H), 7.59-7.65 (m, 1H),7.25-7.28 (d, 1H), 6.97-7.12 (m, 2H), 6.94-6.95 (d, 1H), 4.00-4.23 (m,1H), 3.52-3.65 (m, 4H), 2.69-2.79 (m, 1H), 2.43-2.57 (m, 1H), 2.37 (s,1H), 0.95-2.01 (m, 16H). LC-MS (M+H)⁺=383.3; HPLC purity: 95.38%.

Example 103 1-[3-(1H-indol-3-yl)butanoyl]octahydroquinolin-4(1H)-one(103)

Synthesis of Compound (103)

Compound (103) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(103). ¹H NMR (300 MHz, CDCl3): δ 8.08 (s, 1H), 7.57-7.67 (m, 1H),7.24-7.30 (m, 1H), 6.97-7.11 (m, 3H), 4.45-4.85 (m, 1H), 3.62-3.67 (m,3H), 1.11-3.31 (m, 16H). LC-MS (M+H)⁺=339.2; HPLC purity: 81.37%.

Example 1041-[3-(1H-indol-3-yl)-4-methylpentanoyl]octahydroquinolin-4(1H)-one (104)

Synthesis of Compound (104)

Compound (104) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(104). ¹H NMR (300 MHz, CDCl3): δ 7.94 (s, 1H), 7.55-7.61 (m, 1H),7.23-7.25 (m, 1H), 6.95-7.09 (m, 3H), 4.44-4.84 (m, 1H), 3.63-3.70 (m,1H), 3.14-3.24 (m, 1H), 1.94-2.98 (m, 15H), 1.06-1.08 (d, 3H), 1.00-1.01(d, 3H). LC-MS (M+H)⁺=367.3; HPLC purity: 96.24%.

Example 1051-[3-(1H-indol-3-yl)-4-methylpentanoyl]decahydroquinoline-4-carboxylicacid (105)

Synthesis of methyl1-[3-(1H-indol-3-yl)-4-methylpentanoyl]decahydroquinoline-4-carboxylate(Intermediate-86)

Intermediate-86 was synthesized by following the procedure used to make(49) (Scheme 32).

Synthesis of Compound (105)

Compound (105) was synthesized by following the procedure used to makeIntermediate-3 (Scheme 1). ¹H NMR (300 MHz, CDCl3): δ 7.97-8.00 (d, 1H),7.56-7.59 (d, 1H), 7.23-7.25 (d, 1H), 6.97-7.11 (m, 2H), 6.92-6.93 (d,1H), 4.04-4.21 (m, 1H), 3.37-3.64 (m, 1H), 3.07-3.19 (m, 1H), 2.63-2.90(m, 2H), 1.34-2.28 (m, 14H), 0.94-0.96 (3H), 0.75-0.80 (d, 3H) LC-MS(M+H)⁺=397.2; HPLC purity: 97.21%.

Example 1061-(4-hydroxyoctahydroquinolin-1(2H)-yl)-3-(1H-indol-3-yl)butan-1-one(106)

Synthesis of Compound (106)

Compound (106) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(106). ¹H NMR (300 MHz, CDCl3): δ 7.91 (s, 1H), 7.60-7.62 (d, 1H), 7.27(m, 1H), 7.01-7.13 (m, 2H), 6.95 (s, 1H), 3.89-4.51 (m, 1H), 3.56-3.61(m, 2H), 3.12-3.29 (m, 2H), 1.53-2.76 (m, 13H), 1.36-1.40 (m, 3H). LC-MS(M+H)⁺=341.3; HPLC purity: 89.75%.

Example 1071-[3-(1H-indol-3-yl)-4-methylpentanoyl]decahydroquinoline-4-carboxylicacid sodium salt (107)

Synthesis of Compound (107)

To the stirred solution of Compound (105) (25 mg, 0.063 mmol) in THF,MeOH and water, NaHCO₃ (0.063 mmol) was added at 0° C. The reactionmixture was stirred at RT for 30 minutes. After completion of thereaction, the reaction mixture was concentrated. Resulted crude materialwas triturated with ether to give Compound (107) (24 mg) as white solid.¹H NMR (300 MHz, DMSO-d6): δ 10.90 (s, 1H), 7.44-7.52 (m, 1H), 7.28-7.31(d, 1H), 6.92-7.05 (m, 3H), 4.17 (m, 1H), 3.70-3.90 (m, 1H), 3.165-3.21(m, 4H), 2.64-2.67 (m, 2H), 1.40-2.31 (m, 11H), 0.80-0.90 (m, 6H). LC-MS(M+H)⁺=397.2; HPLC purity: 89.15%.

Example 1084,4,4-trifluoro-3-hydroxy-3-(1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)butan-1-one(108)

Synthesis of Compound (108)

Compound (108) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(108). ¹H NMR (300 MHz, CDCl3): δ 8.15 (s, 1H), 7.70 (m, 1H), 7.29-7.37(m, 3H), 7.08-7.12 (m, 1H), 4.25-4.43 (m, 1H), 3.51-3.62 (m, 1H),3.29-3.37 (m, 1H), 2.76-3.05 (m, 1H), 1.30-1.82 (m, 14H). LC-MS(M+H)⁺=395.1; HPLC purity: 97.32%.

Example 1092-(1H-indol-3-yl)-4-(octahydroquinolin-1(2H)-yl)-4-oxobutanenitrile(109)

Synthesis of Compound (109)

Compound 109) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(109). ¹H NMR (300 MHz, CDCl3): δ 8.15 (s, 1H), 7.61-7.66 (t, 1H),7.32-7.36 (m, 1H), 7.20-7.25 (m, 2H), 7.08-7.17 (m, 1H), 4.66-4.72 (m,1H), 4.40-4.62 (m, 1H), 3.37-3.48 (m, 1H), 2.48-3.13 (m, 3H), 1.30-1.84(m, 13H). LC-MS (M+11)÷=336.1; HPLC purity: 98.95%.

Example 110 3-(1H-indol-3-yl)-3-methyl-2-(octahydroquinolin-1(2H)-ylcarbonyl)butanenitrile (110)

Synthesis of Compound (110)

Compound (110) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(110). ¹H NMR (300 MHz, CDCl3): δ 8.08 (s, 1H), 7.61-7.72 (m, 1H),7.30-7.33 (m, 1H), 7.01-7.16 (m, 3H), 4.35-4.40 (m, 1H), 3.00-3.20 (m,1H), 2.25-2.41 (m, 2H), 1.07-1.78 (m, 19H). LC-MS (M−H)⁺=362.4; HPLCpurity: 95.88%.

Example 1113-(4-fluoro-1H-indol-3-yl)-4-methyl-1-(octahydroquinolin-1(2H)-yl)pentan-1-one(111)

Synthesis of Compound (111)

Compound (111) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(111). ¹H NMR (300 MHz, CDCl3): δ 8.19-8.23 (d, 1H), 7.09-7.12 (d, 1H),7.05 (m, 1H), 6.97 (m, 1H), 6.73-6.81 (m, 1H), 4.36-4.50 (m, 1H),3.59-3.79 (m, 1H), 3.00-3.30 (m, 1H), 2.60-2.96 (m, 2H), 2.10-2.45 (m,1H), 1.00-1.48 (m, 14H), 0.75-0.88 (m, 6H). LC-MS (M+H)⁺=371.2; HPLCpurity: 99.54%.

Example 1123-(4-fluoro-1H-indol-3-yl)-4-methyl-1-(4a-methyloctahydroquinolin-1(2H)-yl)pentan-1-one(112)

Synthesis of Compound (112)

Compound (112) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(112). ¹H NMR (300 MHz, CDCl3): δ 8.28-8.34 (d, 1H), 7.07-7.12 (m, 1H),6.95-7.04 (m, 2H), 6.68-6.76 (m, 1H), 4.12-4.43 (m, 1H), 3.58-3.67 (m,1H), 3.25-3.39 (m, 1H), 2.92-3.00 (m, 1H), 2.68-2.87 (m, 2H), 2.43-2.56(m, 1H), 1.21-2.03 (m, 12H), 0.77-1.04 (m, 9H). LC-MS (M+H)⁺=385.3; HPLCpurity: 98.01%.

Example 1133-(1-methyl-1H-Indol-3-yl)-1-(4a-methyloctahydroquinolin-1(2H)-yl)butan-1-one(113)

Synthesis of Compound (113)

Compound (113) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(113). ¹H NMR (300 MHz, CDCl3): δ 7.56-7.60 (m, 1H), 7.20-7.22 (m, 1H),7.11-7.16 (t, 1H), 6.99-7.04 (t, 1H), 6.80-6.82 (d, 1H), 3.80-3.83 (m,1H), 3.66-3.73 (m, 3H), 3.53-3.62 (m, 1H), 2.64-2.82 (m, 4H), 2.49-2.59(m, 2H), 1.52-2.15 (m, 10H), 1.34-1.42 (m, 6H). LC-MS (M+H)⁺=353.3; HPLCpurity: 88.48%.

Example 1143-(4-fluoro-1H-indol-3-yl)-1-(4a-methyloctahydroquinolin-1(2H)-yl)butan-1-one(114)

Synthesis of Compound (114)

Compound (114) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain (114).¹H NMR (300 MHz, CDCl3): δ 8.13 (s, 1H), 6.96-7.07 (m, 2H), 6.92-6.93(m, 1H), 6.65-6.73 (m, 1H), 4.20-4.48 (m, 1H), 3.38-3.65 (m, 2H),2.80-2.97 (m, 1H), 2.37-2.59 (m, 1H), 1.14-1.97 (m, 16H), 0.76-0.79 (m,3H). LC-MS (M+H)⁺=357.3; HPLC purity: 98.46%.

Example 1153-(4-fluoro-1H-indol-3-yl)-4-methyl-1-(4a-methyloctahydroquinolin-1(2H)-yl)pentan-1-one,peak-1) (115)

Synthesis of Compound (115) (Peak-1)

Mixture of isomers of compound (112) was separated by reverse phase HPLCto give Compound (115) (peak 1). ¹H NMR (300 MHz, CDCl3): δ 8.31 (d,1H), 7.02-7.05 (d, 1H), 6.92-6.99 (m, 1H), 6.85 (s, 1H), 6.62-6.68 (t,1H), 4.05-4.36 (m, 1H), 3.17-3.57 (m, 2H), 2.85-2.95 (m, 2H), 2.66-2.68(m, 1H), 1.58-2.63 (m, 13H), 0.69-0.96 (m, 9H). LC-MS (M+H)⁺=385.3; HPLCpurity: 99.62%. Column: Zorbax eclipse XDB-C18, 4.6×150 mm, 5 μM;RT=16.97 min; Mobile phase: MeCN:H2O (6:4).

Example 1163-(4-fluoro-1H-indol-3-yl)-4-methyl-1-(4a-methyloctahydroquinolin-1(2H)-yl)pentan-1-onepeak-2) (116)

Synthesis of Compound (116) (Peak-2)

Mixture of isomers of compound (112) was separated by reverse phase HPLCto give Compound (116) (peak-2). ¹H NMR (300 MHz, CDCl3): δ 8.47 (s,1H), 7.02-7.05 (d, 1H), 6.87-6.98 (m, 2H), 6.85 (s, 1H), 6.60-6.88 (t,1H), 4.04-4.37 (m, 1H), 3.24-3.60 (m, 1H), 2.85-2.95 (m, 1H), 2.65-2.76(m, 2H), 1.58-2.46 (m, 13H), 0.69-0.96 (m, 9H). LC-MS (M÷H)⁺=385.3; HPLCpurity: 98.53%. Column: Zorbax eclipse XDB-C18, 4.6×150 mm, 51.1M;RT=17.70 min; Mobile phase: MeCN:H2O (6:4).

Example 1173-(1H-indol-3-yl)-4-methyl-1-(octahydroquinolin-1(2H)-yl)pentan-1-one(120)

Synthesis of Compound (117) (peak-1)

Mixture of isomers of compound (95) was separated by using reverse phasepreparative HPLC to give Compound (117) (peak-1). ¹H NMR (300 MHz,CDCl3): δ 7.92 (s, 1H), 7.55-7.63 (m, 1H), 7.25-7.28 (d, 1H), 7.00-7.10(m, 2H), 6.91-6.93 (m, 1H), 4.31-4.47 (m, 1H), 3.34-3.49 (m, 1H),3.04-3.22 (m, 1H), 2.52-2.86 (m, 1H), 2.33-2.37 (m, 2H), 1.08-2.28 (m,14H), 0.90-1.00 (m, 6H). LC-MS (M+H)⁺=353.3; HPLC purity: 97.76%.Column: Zorbax eclipse XDB-C18, 4.6×150 mm, 5 μM; RT=18.77 min; Mobilephase: MeCN: 0.01% TFA in H2O, runtime: 30 minutes.

Example 1183-(1H-indol-3-yl)-4-methyl-1-(octahydroquinolin-1(2H)-yl)pentan-1-one(peak-2) (118)

Synthesis of Compound (118) (peak-2)

Mixture of isomers of compound (95) was separated by using reverse phasepreparative HPLC to give Compound (118) (peak-2). ¹H NMR (300 MHz,CDCl3): δ 7.91 (s, 1H), 7.56-7.59 (m, 1H), 7.24-7.27 (d, 1H), 6.97-7.09(m, 2H), 6.92-6.94 (m, 1H), 4.31-4.46 (m, 1H), 3.34-3.64 (m, 1H),3.17-3.26 (m, 1H), 2.67-2.87 (m, 2H), 2.03-2.41 (m, 1H), 1.08-2.28 (m,14H), 0.91-0.94 (m, 6H). LC-MS (M+H)⁺=353.3; HPLC purity: 97.40%.Column: Zorbax eclipse XDB-C18, 4.6×150 mm, 5 μM; RT=19.07 min; Mobilephase: MeCN: 0.01% TFA in H2O, runtime: 30 minutes.

Example 119 3-(1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)butan-1-one(peak-1) (119)

Synthesis of Compound (119) (Peak-1)

Mixture of isomers of compound (1) was separated by using reverse phasepreparative HPLC to give Compound (119) (peak-1). δ 7.92 (s, 1H),7.58-7.65 (m, 1H), 7.27-7.30 (d, 1H), 7.00-7.13 (m, 2H), 6.93-6.96 (m,1H), 4.30-4.60 (m, 1H), 3.50-3.58 (m, 1H), 2.60-2.90 (m, 1H), 2.30-2.55(m, 2H), 0.78-1.67 (m, 17H). LC-MS (M+H)⁺=325.3; HPLC purity: 99.59%.Column: Zorbax eclipse XDB-C18, 4.6×150 mm, 5 μM; RT=13.37 min; Mobilephase: MeCN:H2O (50:50).

Example 120 3-(1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)butan-1-one(peak-2) (120)

Synthesis of Compound (120) (peak-2)

Mixture of isomers of compound (1) was separated by using reverse phasepreparative HPLC to give Compound (120) (peak-2). ¹H NMR (300 MHz,CDCl3): δ 7.90 (s, 1H), 7.59-7.63 (m, 1H), 7.26-7.30 (d, 1H), 7.00-7.13(m, 2H), 6.94-6.95 (m, 1H), 4.30-4.60 (m, 1H), 3.56-3.65 (m, 1H),2.43-2.89 (m, 3H), 0.79-1.64 (m, 17H). LC-MS (M+H)⁺=325.2; HPLC purity:98.57%. Column: Zorbax eclipse XDB-C18, 4.6×150 mm, 5 μM; RT=14.37 min;Mobile phase: MeCN:H2O (50:50).

Example 1213-(4-fluoro-1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)butan-1-one(121)

Synthesis of Compound (121)

Compound (121) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(121). ¹H NMR (300 MHz, CDCl3): δ 8.85-8.88 (d, 1H), 6.98-7.08 (m, 1H),6.92-6.97 (m, 1H), 6.85 (s, 1H), 6.62-6.72 (m, 1H), 4.41-4.59 (m, 1H),3.54-3.79 (m, 2H), 2.37-3.04 (m, 3H), 1.52-1.63 (m, 6H), 1.46-1.47 (m,2H), 1.37 (s, 5H), 1.32-1.34 (m, 3H). LC-MS (M+H)⁺=343.2; HPLC purity:96.57%.

Example 1223-(4-fluoro-1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)butan-1-one(peak-1) (122)

Synthesis of Compound (122) (peak-1)

Compound (122) (peak-1) was synthesized by following the procedure usedto make Compound (1) (Scheme 2). The crude product was obtained byevaporating the organic layer under reduced pressure and was purified bysilica gel column using Petroleum ether: Ethyl acetate as eluent toobtain Compound (122) (peak-1). ¹H NMR (300 MHz, CDCl3): δ 8.10 (s, 1H),6.96-7.07 (m, 2H), 6.93 (d, 1H), 6.67-6.75 (m, 1H), 4.45-4.59 (m, 1H),3.55-3.69 (m, 2H), 2.41-2.96 (m, 3H), 0.76-1.60 (m, 16H). LC-MS(M+H)⁺=343.2; HPLC purity: 97.18%.

Example 1233-(4-fluoro-1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)butan-1-one(peak-2) (123)

Synthesis of Compound (123) (peak-2)

Compound (123) (peak-2) was synthesized by following the procedure usedto make Compound (1) (Scheme 2). The crude product was obtained byevaporating the organic layer under reduced pressure and was purified bysilica gel column using Petroleum ether: Ethyl acetate as eluent toobtain Compound (123) (peak-2). ¹H NMR (300 MHz, CDCl3): δ 8.08 (s, 1H),6.96-7.07 (m, 2H), 6.93-6.94 (d, 1H), 6.65-6.75 (m, 1H), 4.40-4.59 (m,1H), 3.55-3.69 (m, 2H), 2.41-2.96 (m, 3H), 0.76-1.60 (m, 16H). LC-MS(M+H)⁺=343.2; HPLC purity: 95.41%.

Example 124 3-(1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)butan-1-one(peak-1) (124)

Synthesis of Compound (124) (peak-1)

Compound (124) (peak-1) was synthesized by following the procedure usedto make Compound (1) (Scheme 2). The crude product was obtained byevaporating the organic layer under reduced pressure and was purified bysilica gel column using Petroleum ether: Ethyl acetate as eluent toobtain Compound (124) (peak-1). ¹H NMR (300 MHz, CDCl3): δ 7.93 (s, 1H),7.59-7.65 (m, 1H), 7.27-7.30 (d, 1H), 7.00-7.13 (m, 2H), 6.95 (s, 1H),4.40-4.61 (m, 1H), 3.46-3.65 (m, 2H), 2.37-2.92 (m, 4H), 1.61-1.64 (m,6H), 1.36-1.47 (m, 5H), 1.26-1.29 (m, 4H). LC-MS (M+H)⁺=325.2; HPLCpurity: 93.69%.

Example 125 3-(1H-indol-3-yl)-1-(octahydroquinolin-1(2H)-yl)butan-1-one(peak-2) (125)

Synthesis of (125) (peak-2)

Compound (125) (peak-2) was synthesized by following the procedure usedto make Compound (1) (Scheme 2). The crude product was obtained byevaporating the organic layer under reduced pressure and was purified bysilica gel column using Petroleum ether: Ethyl acetate as eluent toobtain Compound (125) (peak-2). ¹H NMR (300 MHz, CDCl3): δ 7.94 (s, 1H),7.59-7.65 (m, 1H), 7.27-7.30 (d, 1H), 7.02-7.13 (m, 2H), 7.00 (s, 1H),4.40-4.61 (m, 1H), 3.46-3.64 (m, 2H), 2.42-2.97 (m, 4H), 1.64-1.91 (m,6H), 1.41-1.47 (m, 5H), 1.36 (m, 4H). LC-MS (M+H)⁺=325.2; HPLC purity:94.79%.

Example 1263-(4-chloro-1H-indol-3-yl)-1-[trans-(4a,8a)-octahydroquinolin-1(2H)-yl]butan-1-one(126)

Synthesis of Compound (126)

Compound (126) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(126). ¹H NMR (300 MHz, CDCl3): δ 8.32 (s, 1H), 7.12 (s, 1H), 6.99-7.04(m, 3H), 3.68-4.16 (m, 1H), 2.98-3.22 (m, 2H), 2.25-2.85 (m, 1H),0.65-1.85 (m, 18H). LC-MS (M+H)⁺=359.2; HPLC purity: 84.27%.

Example 127 ethyl1-[3-(4-chloro-1H-indol-3-yl)butanoyl]octahydroquinoline-4a(2H)-carboxylate(127)

Synthesis of Compound (127)

Compound (127) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(127). ¹H NMR (300 MHz, CDCl3): δ 8.06 (s, 1H), 6.99-7.02 (m, 4H),3.99-4.10 (m, 5H), 2.66-3.08 (m, 2H), 1.74-2.50 (m, 13H), 1.33-1.36 (m,6H). LC-MS (M+H)⁺=431.2; HPLC purity: 94.82%.

Example 1283-(4-chloro-1H-indol-3-yl)-1-(4a-phenyloctahydroquinolin-1(2H)-yl)butan-1-one(128)

Synthesis of (128)

Compound (128) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(128). ¹H NMR (300 MHz, CDCl3): δ 8.01 (s, 1H), 7.60-7.62 (d, 2H),7.11-7.19 (m, 3H), 7.02 (m, 1H), 6.98 (d, 3H), 3.80-4.21 (m, 2H),3.17-3.23 (m, 1H), 2.80-2.92 (m, 2H), 2.41-2.49 (m, 2H), 0.78-2.15 (m,14H). LC-MS (M+H)⁺=435.2; HPLC purity: 88.09%.

Example 1291-[3-(4-chloro-1H-indol-3-yl)butanoyl]octahydroquinoline-4a(2H)-carboxylicacid (129)

Synthesis of (129)

Compound (129) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(129). ¹H NMR (300 MHz, DMSO-d6): 12.24 (s, 1H), 11.15 (s, 1H),7.24-7.31 (m, 2H), 6.97-7.01 (m, 2H), 3.92-3.95 (m, 1H), 3.26 (m, 2H),2.72-2.76 (m, 2H), 1.21-2.40 (m, 16H). LC-MS (M+H)⁺=403.2; HPLC purity:99.09%.

Example 130 3-(4-chloro-1H-indol-3-yl)-1-[4a-(hydroxymethyl)octahydroquinolin-1(2H)-yl]butan-1-one (130)

Synthesis of (130)

Compound (130) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(130). ¹H NMR (300 MHz, CDCl3): δ 8.10 (s, 1H), 7.16 (m, 1H), 7.02-7.03(d, 1H), 6.98-7.00 (m, 2H), 3.87-4.00 (m, 1H), 3.46-3.71 (m, 1H),2.79-2.98 (m, 3H), 2.44-2.52 (m, 1H), 1.37-1.81 (m, 17H). LC-MS(M+H)⁺=389.2; HPLC purity: 93.28%.

Example 1311-[4a-(hydroxymethyl)octahydroquinolin-1(2H)-yl]-3-(1H-indol-3-yl)butan-1-one(131)

Synthesis of (131)

Compound (131) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(131). ¹H NMR (300 MHz, CDCl3): δ 7.94 (s, 1H), 7.60-7.63 (d, 1H),7.27-7.30 (d, 1H), 7.01-7.13 (m, 2H), 6.96-6.97 (m, 1H), 3.32-3.76 (m,3H), 2.79-2.84 (m, 3H), 2.44-2.62 (m, 2H), 1.62-1.96 (m, 12H), 1.36-1.38(d, 3H). LC-MS (M+H)⁺=355.2; HPLC purity: 97.69%.

Example 1321-(4a-hydroxyoctahydroquinolin-1(2H)-yl)-3-(4-methyl-1H-indol-3-yl)butan-1-one(132)

Synthesis of Compound (132)

Compound (132) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(132). ¹H NMR (300 MHz, CDCl3): δ 7.96 (s, 1H), 7.10-7.13 (m, 1H),6.94-7.01 (m, 2H), 6.76-6.78 (d, 1H), 4.40-4.53 (m, 1H), 3.86-3.95 (m,1H), 3.41-3.66 (m, 1H), 2.71-3.01 (m, 2H), 2.66-2.68 (m, 3H), 2.28-2.60(m, 2H), 1.31-1.99 (m, 14H). LC-MS (M+H)⁺=355.2; HPLC purity: 91.85%.

Example 1333-(1H-indol-3-yl)-4-methyl-1-(octahydro-4H-1,4-benzoxazin-4-yl)pentan-1-one(133)

Synthesis of Compound (133)

Compound (133) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(133). ¹H NMR (300 MHz, CDCl3): δ 7.98 (s, 1H), 7.56-7.58 (d, 1H),7.26-7.28 (d, 1H), 6.97-7.11 (m, 2H), 6.92-6.93 (d, 1H), 4.01-4.22 (m,1H), 3.29-3.57 (m, 3H), 3.10-3.25 (m, 2H), 2.64-2.94 (m, 2H), 1.99-2.39(m, 1H), 1.67-1.84 (m, 1H), 1.15-1.21 (m, 5H), 0.95-0.99 (m, 4H),0.76-0.83 (m, 5H). LC-MS (M+H)⁺=355.2; HPLC purity: 98.87%.

Example 1344-methyl-3-(1-methyl-1H-indol-3-yl)-1-(octahydro-4H-1,4-benzoxazin-4-yl)pentan-1-one(134)

Synthesis of Compound (134)

Compound (134) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(134). ¹H NMR (300 MHz, CDCl3): δ 7.53-7.56 (d, 1H), 7.19-7.21 (d, 1H),7.08-7.13 (t, 1H), 6.95-7.02 (m, 1H), 6.77 (s, 1H), 3.76-4.16 (m, 1H),3.66 (s, 3H), 3.47-3.55 (m, 1H), 3.27-3.42 (m, 2H), 3.09-3.20 (m, 2H),2.62-2.92 (m, 3H), 2.24-2.35 (m, 1H), 1.94-2.17 (m, 2H), 1.51-1.80 (m,6H), 0.93-0.97 (m, 3H), 0.76-0.80 (m, 3H). LC-MS (M+H)⁺=369.3; HPLCpurity: 91.33%.

Example 1353-(4-fluoro-1H-indol-3-yl)-4-methyl-1-(octahydro-4H-1,4-benzoxazin-4-yl)pentan-1-one(135)

Synthesis of Compound (135)

Compound (135) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(135). ¹H NMR (300 MHz, CDCl3): δ 8.22 (s, 1H), 6.98-7.13 (m, 3H),6.70-6.76 (m, 1H), 4.07-4.22 (m, 1H), 3.10-3.83 (m, 3H), 2.70-2.88 (m,2H), 2.04-2.13 (m, 1H), 1.66-1.86 (m, 3H), 0.77-1.33 (m, 14H). LC-MS(M+H)⁺=373.2; HPLC purity: 94.76%.

Example 1363-(4-fluoro-1H-indol-3-yl)-1-(octahydro-4H-1,4-benzoxazin-4-yl)butan-1-one(136)

Synthesis of Compound (136)

Compound (136) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(136). ¹H NMR (300 MHz, CDCl3): δ 8.08 (s, 1H), 6.96-7.12 (m, 3H),6.68-6.77 (m, 1H), 3.87-4.28 (m, 1H), 3.24-3.87 (m, 2H), 2.64-2.96 (m,2H), 2.42-2.56 (m, 1H), 2.21-2.30 (m, 1H), 1.32-2.02 (m, 13H). LC-MS(M+H)⁺=345.2; HPLC purity: 94.02%.

Example 1373-(4-fluoro-1H-indol-3-yl)-1-(octahydro-4H-1,4-benzoxazin-4-yl)butan-1-one(peak-1) (137)

Synthesis of Compound (137) (peak-1)

Mixture of isomers of Compound (136) was separated by using preparativereverse phase HPLC column to give Compound (137) (peak-1). ¹H NMR (300MHz, CDCl3): δ 8.26-8.33 (d, 1H), 6.91-7.10 (m, 3H), 6.65-6.76 (m, 1H),4.11-4.29 (m, 1H), 3.58-3.78 (m, 1H), 3.54-3.58 (m, 1H), 3.29-3.42 (m,2H), 3.08-3.15 (m, 1H), 2.77-3.03 (m, 2H), 2.34-2.55 (m, 2H), 1.78-1.91(m, 1H), 1.52-1.67 (m, 3H), 1.32-1.41 (m, 6H). LC-MS (M+H)⁺=345.2; HPLCpurity: 97.60%; Column: Zorbax eclipse XDB-C18, Mobile phase: MeCN:H2O,40:60, RT=14.93 min.

Example 1383-(4-fluoro-1H-indol-3-yl)-1-(octahydro-4H-1,4-benzoxazin-4-yl)butan-1-one(peak-2) (138)

Synthesis of Compound (138) (peak-2)

Mixture of isomers of Compound (136) was separated by using preparativereverse phase HPLC column to give Compound (138) (peak-2). ¹H NMR (300MHz, CDCl3): δ 8.14 (s, 1H), 6.93-7.12 (m, 3H), 6.65-6.74 (m, 1H),4.13-4.28 (m, 1H), 3.44-3.86 (m, 2H), 3.18-3.38 (m, 2H), 2.57-2.88 (m,2H), 2.43-2.52 (m, 1H), 1.84-2.33 (m, 2H), 1.56-1.88 (m, 4H), 1.33-1.40(m, 6H). LC-MS (M+H)⁺=345.2; HPLC purity: 96.43%; column: Zorbax eclipseXDB-C18, Mobile phase: MeCN:H2O, 40:60, RT=15.46 min.

Example 1393-(4-fluoro-1H-indol-3-yl)-1-[cis-(4a,8a)-octahydro-4H-1,4-benzoxazin-4-yl]butan-1-one(peak-1) (139)

Synthesis of Compound (139) (peak-1)

Compound (139) (peak-1) was synthesized by following the procedure usedto make Compound (1) (Scheme 2). The crude product was obtained byevaporating the organic layer under reduced pressure and was purified bysilica gel column using Petroleum ether: Ethyl acetate as eluent toobtain, Compound (139) (peak-1). ¹H NMR (300 MHz, CDCl3): δ 8.03 (s,1H), 6.92-7.10 (m, 3H), 6.72-6.77 (m, 1H), 4.10-4.30 (m, 1H), 3.54-3.76(m, 2H), 2.46-3.27 (m, 7H), 1.67-1.79 (m, 4H), 1.33-1.41 (m, 6H). LC-MS(M+H)⁺=345.2; HPLC purity: 96.25%.

Example 1403-(4-fluoro-1H-indol-3-yl)-1-[cis-(4a,8a)-octahydro-4H-1,4-benzoxazin-4-yl]butan-1-one(peak-2) (140)

Synthesis of Compound (140)

Compound (140) (peak-2) was synthesized by following the procedure usedto make Compound (1) (Scheme 2). The crude product was obtained byevaporating the organic layer under reduced pressure and was purified bysilica gel column using Petroleum ether: Ethyl acetate as eluent toobtain Compound (140) (peak-2). ¹H NMR (300 MHz, CDCl3): δ 8.03 (s, 1H),6.92-7.07 (m, 3H), 6.7-6.77 (m, 1H), 4.10-4.30 (m, 1H), 3.54-3.76 (m,2H), 2.-3.27 (m, 7H), 1.67-1.83 (m, 4H), 1.33-1.41 (m, 6H). LC-MS(M+H)⁺=345.2; HPLC purity: 97.10%.

Example 141 ethyl1-[3-(1,3-benzothiazol-2-yl)butanoyl]octahydroquinoline-4a(2H)-carboxylate(141)

Synthesis of Compound (141)

Compound (141) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(141). ¹H NMR (300 MHz, CDCl3): δ 7.75-7.89 (m, 2H), 7.23-7.38 (m, 2H),3.81-4.13 (m, 3H), 2.99-3.09 (m, 1H), 2.53-2.87 (m, 1H), 2.01-2.19 (m,3H), 1.22-1.78 (m, 18H). LC-MS (M+H)⁺=415.2; HPLC purity: 93.99%.

Example 1423-(1,3-benzothiazol-2-yl)-1-(octahydro-1H-indol-1-yl)butan-1-one (142)

Synthesis of Compound (142)

Compound (142) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(142). ¹H NMR (300 MHz, CDCl3): δ 7.88-7.91 (d, 1H), 7.75-7.78 (d, 1H),7.35-7.40 (t, 1H), 7.25-7.30 (t, 1H), 3.86-4.10 (m, 2H), 3.38-3.50 (m,2H), 2.91 (m, 1H), 2.56 (m, 1H), 1.05-2.06 (m, 14H). LC-MS (M+H)+329.2;HPLC purity: 97.29%.

Example 1431-(octahydroquinolin-1(2H)-yl)-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)butan-1-one(143)

Synthesis of Compound (143)

Compound (143) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(143). ¹H NMR (300 MHz, CDCl3): δ 9.63 (s, 1H), 7.94-8.14 (m, 2H),6.97-7.07 (m, 2H), 4.40-4.60 (m, 1H), 3.40-3.65 (m, 2H), 2.41-2.88 (m,5H), 1.18-1.48 (m, 14H). LC-MS (M+H)⁺=326.1; HPLC purity: 94.48%.

Example 1441-(octahydroquinolin-1(2H)-yl)-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)butan-1-one(peak-1) (144)

Synthesis of Compound (144) (Peak-1)

Mixture of isomers of Compound (143) was separated by using preparativereverse phase HPLC column to give Compound (144) (peak-1). ¹H NMR (300MHz, CDCl3): δ 12.04 (s, 1H), 8.55-8.57 (d, 1H), 8.14-8.16 (d, 1H),7.30-7.34 (m, 2H), 4.32-4.67 (m, 1H), 3.47-3.85 (m, 2H), 2.51-2.98 (m,5H), 1.32-1.73 (m, 14H). LC-MS (M+H)⁺=326.2; HPLC purity: 99.85%;Column: Zorbax eclipse XDB-C-18, mobile phase: MeCN:H2O 50:50, RT=4.77min.

Example 1451-(octahydroquinolin-1(2H)-yl)-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)butan-1-one(peak-2) (145)

Synthesis of Compound (145) (Peak-2)

Mixture of isomers of Compound (143) was separated by using preparativereverse phase HPLC column to give Compound (145) (peak-2). ¹H NMR (300MHz, CDCl3): δ 11.84 (s, 1H), 8.51-8.54 (d, 1H), 8.16 (d, 1H), 7.30 (m,2H), 4.32-4.67 (m, 1H), 3.45-3.76 (m, 2H), 2.51-2.98 (m, 5H), 1.32-1.73(m, 14H). LC-MS (M+H)⁺=326.2; HPLC purity: 98.76%; Column: Zorbaxeclipse XDB-C-18, mobile phase: MeCN:H2O 50:50, RT=5.24 min.

Example 1461-[4a-(hydroxymethyl)octahydroquinolin-1(2H)-yl]-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)butan-1-one(146)

Synthesis of Compound (146)

Compound (146) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(146). ¹H NMR (300 MHz, DMSO-d6): δ 11.28 (s, 1H), 8.15-8.17 (d, 1H),7.93-7.96 (d, 1H), 6.99-7.25 (m, 2H), 3.90-4.25 (m, 1H), 3.39-3.70 (m,3H), 2.84-2.93 (m, 2H), 2.58-2.75 (m, 4H), 1.24-2.03 (m, 14H). LC-MS(M+H)⁺=356.2; HPLC purity: 96.35%.

Example 1473-(4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-[4a-(hydroxymethyl)octahydroquinolin-1(2H)-yl]butan-1-one (147)

Synthesis of Compound (147)

Compound (147) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(147). ¹H NMR (300 MHz, CDCl3): δ 9.07 (s, 1H), 8.05-8.07 (d, 1H),6.99-7.10 (m, 2H), 3.51-3.92 (m, 4H), 2.78-2.94 (m, 4H), 2.14-2.32 (m,2H), 1.35-1.96 (m, 13H). LC-MS (M+H)⁺=390.2; HPLC purity: 91.09%.

Example 1481-(4a-hydroxyoctahydroquinolin-1(2H)-yl)-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)butan-1-one(148)

Synthesis of Compound (148)

Compound (148) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(148). ¹H NMR (300 MHz, DMSO-d6): δ 11.28 (s, 1H), 8.16 (d, 1H),7.95-7.99 (m, 1H), 7.20-7.24 (m, 1H), 6.99-7.03 (m, 1H), 4.35 (s, 1H),4.15-4.29 (m, 1H), 3.63-3.72 (m, 1H), 3.42-3.51 (m, 2H), 2.62-2.83 (m,3H), 1.20-1.98 (m, 14H). LC-MS (M+H)⁺=342.2; HPLC purity: 98.98%.

Example 1491-[3-(4-methyl-1H-indol-3-yl)butanoyl]octahydroquinoline-4a(2H)-carbonitrile(149)

Synthesis of Compound (149)

Compound (149) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(149). ¹H NMR (300 MHz, CDCl3): δ 6.98-7.05 (m, 2H), 6.75-6.78 (m, 2H),4.82 (s, 1H), 3.93 (s, 1H), 3.63 (s, 3H), 3.16-3.22 (m, 2H), 2.64 (s,3H), 2.55-2.61 (m, 2H), 1.97-2.01 (m, 2H), 1.75-1.79 (m, 2H), 1.70-1.72(m, 3H), 1.59-1.65 (m, 7H). LC-MS (M+H)⁺=364.2; HPLC purity: 93.73%.

Example 1501-[3-(4-fluoro-1H-indol-3-yl)-3-phenylpropanoyl]decahydroquinoline-4-carboxylicacid (150)

Synthesis of Compound (150)

Compound (150) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). ¹H NMR (300 MHz, DMSO-d6): δ 12.23 (s, 1H),11.17 (s, 1H), 7.34-7.36 (d, 1H), 7.18-7.27 (m, 4H), 7.09-7.15 (m, 2H),6.93-7.00 (m, 1H), 6.58-6.64 (m, 1H), 4.83 (m, 1H), 3.91-4.06 (m, 1H),3.00-3.18 (m, 3H), 1.09-1.88 (m, 13H). LC-MS (M+H)⁺=449.2; HPLC purity:96.20%.

Example 1511-[3-(6-fluoro-1H-indol-3-yl)-3-phenylpropanoyl]decahydroquinoline-4-carboxylicacid (151)

Synthesis of Compound (151)

Compound (151) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). ¹H NMR (300 MHz, DMSO-d6): δ 12.21 (s, 1H),10.94 (s, 1H), 7.27-7.30 (m, 4H), 7.19-7.24 (t, 2H), 7.05-7.13 (m, 2H),6.69-6.75 (m, 1H), 4.63-4.65 (m, 1H), 3.90-3.98 (m, 2H), 2.98-3.26 (m,3H), 2.27-2.43 (m, 2H), 1.10-1.84 (m, 10H). LC-MS (M+H)⁺=449.22; HPLCpurity: 96.21%.

Example 1521-[3-(1,3-benzothiazol-2-yl)-3-phenylpropanoyl]decahydroquinoline-4-carboxylicacid (152)

Synthesis of Compound (152)

Compound (152) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). ¹H NMR (300 MHz, DMSO-d6): δ 12.26 (s, 1H),7.92-8.00 (m, 2H), 7.24-7.49 (m, 7H), 4.96-4.98 (m, 1H), 3.50-4.23 (m,3H), 2.90-3.21 (m, 1H), 1.47-2.27 (m, 13H). LC-MS (M+H)⁺=449.1; HPLCpurity: 99.48%.

Example 1531-(4a-methoxyoctahydroquinolin-1(2H)-yl)-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)butan-1-one(153)

Synthesis of Compound (153)

Compound (153) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(153). ¹H NMR (300 MHz, CDCl3): δ 9.14 (s, 1H), 8.20-8.21 (d, 1H),7.93-7.96 (m, 1H), 6.96-7.08 (m, 2H) 3.44-3.64 (m, 3H), 303-3.06 (m,3H), 2.42-2.75 (m, 2H), 1.27-1.83 (m, 16H). LC-MS (M+H)⁺=356.2; HPLCpurity: 94.26%.

Example 1541-[3-(1,3-benzothiazol-2-yl)butanoyl]decahydroquinoline-4-carboxylicacid (154)

Synthesis of Compound (154)

Compound (154) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). ¹H NMR (300 MHz, CD3OD): δ 7.88-7.94 (m,2H), 7.44-7.50 (m, 1H), 7.35-7.41 (m, 1H), 4.17 (s, 1H), 3.79-3.97 (m,2H), 3.52-3.63 (m, 1H), 3.07-3.22 (m, 1H), 2.69-2.86 (m, 1H), 2.56 (m,1H) 2.04-2.11 (m, 2H), 1.88-1.92 (m, 2H), 1.61 (m, 4H), 1.45-1.51 (m,3H), 1.35-1.38 (m, 4H). LC-MS (M+H)⁺=387.2; HPLC purity: 93.02%.

Example 1551-[3-(4-chloro-1H-indol-3-yl)-3-phenylpropanoyl]decahydroquinoline-4-carboxylicacid (155)

Synthesis of (155)

Compound (155) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 12.19 (brs,1H), 11.31 (s, 1H), 7.49, brs, 1H), 7.20-7.31 (m, 5H), 7.09-7.11 (m,1H), 6.96-7.01 (t, 1H), 6.85-6.87 (d, 1H), 5.27-5.30 (m, 1H), 3.81-3.91(2H, m), 2.60-2.95 (m, 3H), 2.25 (brs, 1H), 1.39-1.95 (m, 11H). LC-MS(M+H)⁺=465.2; HPLC purity: 99.0%.

Example 1561-[3-(4-fluoro-1H-indol-3-yl)-3-(thiophen-2-yl)propanoyl]decahydroquinoline-4-carboxylicacid (160)

Synthesis of (156):

Compound (156) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 8.28 (brs, 1H),6.98-7.06 (m, 4H), 6.80-6.82 (m, 2H), 6.62-6.68 (m, 1H), 5.06-5.20 (m,1H), 4.46-4.59 (m, 1H), 3.94-4.06 (m, 1H) 3.54-3.64 (1H), 3.30-3.42 (m,1H), 3.04-3.16 (m, 2H), 2.27-2.55 (m, 1H), 1.59-1.87 (m, 6H), 1.35-1.40(m, 4H). LC-MS (M+H)⁺=455.2; HPLC purity: 98.58%.

Example 157 1-[3-(4-fluoro-1H-indol-3-yl)-3-(4-fluorophenyl)propanoyl]decahydroquinoline-4-carboxylic acid (157)

Synthesis of (157)

Compound (157) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 12.23 (brs,1H), 11.19 (brs, 1H), 7.24-7.53 (m, 3H), 7.12-7.15 (d, 1H), 6.94-7.06(m, 3H), 6.61-6.65 (m, 1H), 4.83 (brs, 1H), 3.87-4.06 (m, 1H), 2.92-3.20(4H), 2.45-2.60 (m, 2H), 1.47-1.86 (m, 10H). LC-MS (M+H)⁺=467.2; HPLCpurity: 97.74%.

Example 1581-[3-(4-chloro-1H-indol-3-yl)butanoyl]decahydroquinoline-4-carboxylicacid (158)

Synthesis of (158)

Compound (158) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 12.25 (brs,1H), 11.19 (brs, 1H), 7.28-7.32 (m, 2H), 6.96-7.04 (m, 2H), 3.96-4.01(m, 2H), 3.45-3.50 (m, 1H), 2.63-2.79 (4H), 1.91-1.95 (m, 1H), 1.23-1.70(m, 13H). LC-MS (M+H)⁺=403.2; HPLC purity: 93.16%.

Example 1591-[3-(6-fluoro-1H-indol-3-yl)-3-phenylpropanoyl]decahydroquinoline-4-carboxylicacid (peak-1) (159)

Synthesis of3-(6-fluoro-1H-indol-3-yl)-N-[(1R)-2-hydroxy-1-phenylethyl]-3-phenylpropanamide(Intermediate-88, peak-1 and Intermediate-89 peak-2)

At 0° C., to a stirred solution of Intermediate-87 (0.800 g, 2.8 mmol)and Starting Material-31 (0.387 g, 2.8 mmol) in THF: DMF (10 mL: 0.5mL), HBTU (1.28 g, 3.3 mmol) was added followed by addition of isopropylethylamine (1.09 g, 8.4 mmol). The resulted reaction mixture was stirredat room temperature for 2 hours. After completion of the reaction(reaction monitored by TLC), the reaction mass was quenched with waterand extracted with Ethyl acetate (3×50 mL). The organic layer was washedwith saturated brine solution (50 mL) and concentrated. Crude productwas purified by combi flash chromatography eluting with hexanes:EtOAc(1:1) to give Intermediate-88 (200 mg) and Intermediate-89 (280 mg) aspink solid.

Intermediate-88, peak-1

LC-MS (M+H)⁺=403.2; HPLC purity: 91.08%; Column: Zorbax eclipse XDB-C18,4.6×50 mm, 5 μm; RT=13.58 minutes, Mobile phase: MeCN: 0.01% TFAgradient.

Intermediate-89, peak-2

LC-MS (M+H)⁺=403.2; HPLC purity: 91.62%; Column: Zorbax eclipse XDB-C18,4.6×50 mm, 5 μm; RT=13.82 minutes, Mobile phase: MeCN: 0.01% TFAgradient.

Synthesis of 3-(6-fluoro-1H-indol-3-yl)-3-phenylpropanoic acid(Intermediate-90, peak-1)

To a stirred solution of Intermediate-88, peak-1 (0.200 g, 0.49 mmol) in1,4 dioxane: H₂O (2 mL: 2 mL) Conc. H₂SO₄ (0.6 mL) was added and theresultant mixture was heated at 90° C. for 6 hours. After completion ofthe reaction (reaction monitored by TLC), the reaction mass was quenchedwith ice and extracted with Ethyl acetate (3×50 mL). The organic layerwas washed with saturated brine solution (50 mL) and dried overanhydrous Na₂SO₄ and concentrated to give Intermediate-90 (130 mg) as apink oily material.

Synthesis of methyl1-[3-(6-fluoro-1H-indol-3-yl)-3-phenylpropanoyl]decahydroquinoline-4-carboxylate(Intermediate-91, peak-1)

Intermediate-91, peak-1 was synthesized by following the procedure usedto make Compound (1) (Scheme 2).

Synthesis of Compound (159) (peak-1)

Compound (159) (peak-1) was synthesized by following the procedure usedto make Compound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 12.21(brs, 1H), 10.93 (brs, 1H), 7.22-7.29 (m, 3H), 7.05-7.13 (m, 3H),6.93-6.97 (m, 2H), 6.75-6.80 (m, 1H), 4.56-4.64 (m, 1H), 3.50-3.60 (m,2H), 2.99-3.1 (m, 3H), 2.27-2.32 (m, 1H), 1.15-1.83 (m, 11H). LC-MS(M+H)⁺=449.2; HPLC purity: 96.66%.

Example 1601-[3-(6-fluoro-1H-indol-3-yl)-3-phenylpropanoyl]decahydroquinoline-4-carboxylicacid (peak-2) (160)

Synthesis of 3-(6-fluoro-1H-indol-3-yl)-3-phenylpropanoic acid(Intermediate-92, peak-2)

Intermediate-92 (peak-2) was synthesized by following the procedure usedto make Intermediate-90 (peak-1) (Scheme 54).

Synthesis of methyl1-[3-(6-fluoro-1H-indol-3-yl)-3-phenylpropanoyl]decahydroquinoline-4-carboxylate(Intermediate-93, peak-2)

Intermediate-93 (peak-2) was synthesized by following the procedure usedto make Compound (1) (Scheme 2).

Synthesis of Compound (160) (peak-2)

Compound (160) (peak-2) was synthesized by following the procedure usedto make Compound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 12.22(brs, 1H), 10.94 (brs, 1H), 7.19-7.31 (m, 3H), 7.05-7.13 (m, 3H),7.05-7.11 (m, 2H), 6.69-6.75 (m 1H), 4.62-4.65 (m, 1H), 3.78-3.93 (m,1H), 2.97-3.18 (m, 4H), 2.41-2.45 (m, 1H), 1.46-1.90 (m, 11H). LC-MS(M+H)⁺=449.2; HPLC purity: 97.44%.

Example 1611-[3-(4-fluoro-1H-indol-3-yl)-3-phenylpropanoyl]decahydroquinoline-4-carboxylicacid (peak-1) (161)

Synthesis of Compound (161) (Peak-1)

Compound (161) (peak-1) was synthesized by following the procedure usedto make Compound (159) (peak-2) (Scheme 53, & 54). 1H NMR (300 MHz,CDCl3): δ 8.38 (brs, 1H), 6.90-7.35 (m, 8H), 6.55-6.61 (m, 1H),4.86-4.93 (m, 1H), 3.73-3.93 (m, 1H), 3.31-3.36 (m, 1H), 2.98-3.08 (m,3H), 2.22-2.35 (m, 1H), 1.31-1.69 (m, 11H). LC-MS (M+H)⁺=449.2; HPLCpurity: 97.90%.

Example 1621-[3-(4-fluoro-1H-indol-3-yl)-3-phenylpropanoyl]decahydroquinoline-4-carboxylicacid (peak-2) (162)

Synthesis of Compound (162) (peak-2)

Compound (162) (peak-2) was synthesized by following the procedure usedto make Compound (160) (peak-2) (Scheme 55). 1H NMR (300 MHz, DMSO-d6):δ 12.23 (brs, 1H), 11.18 (brs, 1H), 7.35-7.36 (m, 1H), 7.07-7.27 (m,6H), 6.93-7.00 (m, 1H), 6.51-6.71 (dd, 1H), 4.83 (brs, 1H), 3.91-3.99(m, 1H), 2.92-3.20 (m, 3H), 2.41-2.45 (m, 2H), 1.45-1.88 (m, 11H). LC-MS(M+H)⁺=449.2; HPLC purity: 98.50%.

Example 1631-[4-methyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)pentanoyl]decahydroquinoline-4-carboxylic acid (163)

Synthesis of Compound (163)

Compound (163) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): 12.22 (brs, 1H),11.30 (brs, 1H), 8.13-8.14 (d, H), 7.94-7.96 (d, 1H), 7.19-7.20 (m, 1H),6.97-7.01 (m, 1H), 3.82-4.04 (m, 1H), 3.16-3.21 (m, 2H), 2.71-2.84 (m,5H), 2.20-2.25 (m, 1H), 1.40-2.03 (m, 6H), 1.17-1.23 (4H), 0.90-0.92 (d,3H), 0.56-0.58 (d, 3H). LC-MS (M+H)⁺=396.2; HPLC purity: 95.12%.

Example 1644-methyl-1-(octahydroquinolin-1(2H)-yl)-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)pentan-1-one(164)

Synthesis of Compound (164)

Compound (164) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(164). 1H NMR (300 MHz, CDCl3): δ 9.46 (brs, 1H), 8.17-8.21 (m, 1H),7.89-7.95 (m, 1H), 6.95-7.05 (m, 2H), 4.29-4.45 (m, 1H), 3.35-3.65 (m,2H), 3.09-3.25 (m, 1H), 2.69-2.89 (m, 3H), 2.29-2.37 (m, 1H), 1.95-2.12(m, 3H0, 1.55-1.70 (m, 3H), 1.37-1.49 (m, 6H), 0.90-0.92 (d, 3H),0.76-0.78 (d, 3H). LC-MS (M+H)⁺=354.3; HPLC purity: 96.20%.

Example 1651-[3-(1H-pyrrolo[2,3-b]pyridin-3-yl)butanoyl]decahydroquinoline-4-carboxylicacid (165)

Synthesis of Compound (165)

Compound (165) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 12.22 (brs,1H), 11.31 1H), 8.15-8.16 (m, H), 7.95-7.98 (d, 1H), 7.25-7.26 (m, 1H),6.98-7.02 (m, 1H), 4.05-4.06 (m, 1H), 3.74-3.87 (m, 1H), 3.48-3.52 (m,2H), 2.63-2.81 (m, 3H), 2.27-2.34 (m, 1H), 1.60-1.98 (m, 8H), 1.45-1.49(m, 2H), 1.25-1.28, m, 3H). LC-MS (M+H)⁺=370.2; HPLC purity: 91.67%.

Example 1663-(4-chloro-1H-benzotriazol-1-yl)-1-(octahydroquinolin-1(2H)-yl)butan-1-one(166)

Synthesis of Compound (166)

Compound (166) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(166). ¹H NMR (300 MHz, CD3OD) 1H NMR (300 MHz, CDCl3): δ 7.49-7.54 (t,1H), 7.26-7.35 (m, 2H), 5.40-5.44 (m, 1H), 4.23-4.38 (m, 1H), 3.30-3.76(m, 2H0, 2.71-3.02 (m, 1.5H), 2.41-2.51 (m, 0.5H), 1.18-1.75 (m, 16H):LC-MS: (M+H)+=361.1; HPLC purity=89.09%.

Example 1673-(4-chloro-2H-benzotriazol-2-yl)-1-(octahydroquinolin-1(2H)-yl)butan-1-one(167)

Synthesis of Compound (167)

Compound (167) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(167). 1H NMR (300 MHz, CDCl3): δ 7.67-7.71 (m, 1H), 7.28-7.31 (M, 1H),7.19-7.24 (m, 1H), 5.55-5.64 (m, 1H), 4.38-4.55 (m, 1H), 3.50-3.62 (m,1H), 3.20-3.45 (m, 1H), 2.75-3.05 (m, 2H), 2.46-2.50 (m, 1H), 1.70 (d,3H), 1.17-1.68 (m, 12H). LC-MS: (M+H)+=361.2; HPLC purity=95.89%.

Example 1681-[3-(4-methyl-1H-benzotriazol-1-yl)butanoyl]decahydroquinoline-4-carboxylicacid (168)

Synthesis of Compound (168)

Compound (168) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 7.66-7.69 (d,1H), 7.37-7.42 (t, 1H), 7.14-7.16 (d, 1H), 5.41 (brs, 1H), 3.70-3.86 (m,3H), 2.66 (s, 3H), 2.45-2.51 (m, 2H), 2.27 (brs, 1H), 1.19-1.83 (m,14H). LC-MS: (M+H)+=385.2; HPLC purity=83.84%.

Example 1691-[3-(4-methyl-2H-benzotriazol-2-yl)butanoyl]decahydroquinoline-4-carboxylicacid (169)

Synthesis of Compound (169)

Compound (169) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): 12.26 (brs, 1H),7.65-7.70 (1H, m), 7.37-7.42 (t, 1H), 7.14-7.16 (d, 1H), 5.41-5.43 (m,1H), 3.88-3.96 (m, 2H), 2.85-3.12 (m, 3H0, 2.69 (s, 3H), 2.27 (brs, 1H),1.70-2.0 (m, 11H), 1.61 (d, 3H). LC-MS: (M+H)+=385.2; HPLCpurity=84.25%.

Example 1701-[3-(4-fluoro-1H-indol-3-yl)-3-(thiophen-2-yl)propanoyl]decahydroquinoline-2-carboxylicacid (170)

Synthesis of Compound (170)

Compound (170) was synthesized by following the procedure used to make(105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 11.18 (brs, 1H),7.35-7.40 (m, 1H), 7.13-7.28 (m, 2H), 6.98-7.02 (m, 1H), 6.80-6.88 (m,2H), 6.65-6.71 (m, 1H), 5.00-5.12 (m, 1H), 4.59-4.66 (m, 0.5H),(4.26-4.34 (m, 0.5H), 3.80-3.86 (m, 1H), 2.92-3.05 (m, 2H), 2.20-2.22(m, 1H), 1.33-1.75 (m, 10H). LC-MS: (M+H)+=455.1; HPLC purity=97.36%.

Example 1711-[3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)butanoyl]decahydroquinoline-4-carboxylicacid (171)

Synthesis of (171)

Compound (171) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 12.26 (brs,1H), 11.77 (s, 1H), 8.09-8.11 (d, 1H), 7.42 (s, 1H), 7.10-7.12 (d, 1H),4.05 (brs, 1H), 3.85-3.87 (m, 2H), 3.45-3.51 (m, 2H), 2.66-2.76 m, 2H),1.62-1.97 (m, 11H), 1.40-1.43 (d, 3H). LC-MS: (M+H)+=404.2; HPLCpurity=90.05%

Example 1724-methyl-3-(4-methyl-1H-benzotriazol-1-yl)-1-(octahydroquinolin-1(2H)-yl)pentan-1-one(172)

Synthesis of Compound (172)

Compound (172) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(172) 1H NMR (300 MHz, CDCl3): δ 7.34-7.39 (m, 1H), 7.25-7.30 (m, 1H),7.00-7.02 (m, 1H), 5.00-5.03 (m, 1H), 4.61 (brs, 0.5H), 4.15-4.30 (m,0.5H), 3.41-3.61 (m, 2H), 2.78-3.01 (m, 1H), 2.70 (s, 3H), 2.15-2.42 (m,1H), 1.32-1.95 (m, 14H), 0.70-0.81 (m, 6H). LC-MS: (M+H)+=369.3; HPLCpurity=82.9%

Example 1733-(4-chloro-1,3-benzothiazol-2-yl)-1-(octahydroquinolin-1(2H)-yl)butan-1-one(173)

Synthesis of Compound (173)

Compound (173) was synthesized by following the procedure used to makeCompound (1) (Scheme 2). The crude product was obtained by evaporatingthe organic layer under reduced pressure and was purified by silica gelcolumn using Petroleum ether: Ethyl acetate as eluent to obtain Compound(173) 1H NMR (300 MHz, CDCl3): δ 7.64-7.67 (d, 1H), 7.36-7.39 (d, 1H),7.16-7.21 (m, 1H), 4.39-4.56 (m, 1H), 3.64-3.94 (m, 2H), 3.01-3.23 (m,2H), 2.48-2.65 (m, 2H), 1.52-1.78 (m, 8H), 1.46 (d, 3H), 1.31-142 (m,6H). LC-MS: (M+H)+=377.1; HPLC purity=98.83%

Example 1741-[3-(6-fluoro-1H-indol-3-yl)-3-phenylpropanoyl]decahydroquinoline-2-carboxylicacid (174)

Synthesis of Compound (174)

Compound (174) was synthesized by following the procedure used to makeCompound (105) (Scheme 51) 1H NMR (300 MHz, CDCl3): δ 8.06 (brs, 0.5H),7.98 (brs, 0.5H), 7.22-7.24 (m, 2H), 6.91-6.98 (m, 5H), 6.60-6.75 (m,2H), 4.85-4.87 (m, 1H), 4.78-4.83 (m, 2H), 3.54-3.66 (m, 2H), 3.24-3.32(dd, 1H), 3.03-3.10 (dd, 1H), 2.12-2.30 (m, 2H), 1.85-2.00 (m, 5H),1.41-1.58 (m, 4H). LC-MS: (M+H)+=449.2; HPLC purity=93.61%.

Example 1751-[3-(6-fluoro-1H-indol-3-yl)-3-phenylpropanoyl]decahydroquinoline-3-carboxylicacid (175)

Synthesis of Compound (175)

Compound (175) was synthesized by following the procedure used to makeCompound (105) (Scheme 51) 1H NMR (300 MHz, DMSO-d6): 12.35 (brs, 1H),10.99 (brs, 1H), 7.20-7.31 (m, 6H), 7.05-7.12 (m, 2H), 6.69-6.75 (t,1H), 4.62-4.66 (m, 1H), 4.30-4.45 (m, 0.5H), 3.81-4.10 (m, 0.5H),2.93-3.22 (m, 2H), 2.45-2.51 (m, 2H), 2.24-2.30 (m, 1H), 1.17-1.75 (m,11H). LC-MS: (M+H)+=449.2.

Example 1761-[3-(4-fluoro-1H-indol-3-yl)-3-phenylpropanoyl]decahydroquinoline-3-carboxylicacid (176)

Synthesis of Compound (176)

Compound (176) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 8.19 (brs, 1H),7.19-7.23 (m, 1H), 6.92-7.12 (m, 7H), 6.54-6.65 (m, 1H), 4.88-4.90 (m,1H), 4.51-4.64 (m, 1H), 3.66-3.79 (m, 1H), 2.94-3.09 (m, 2H), 2.48-2.74(m, 2H), 2.12-2.30 (m, 1H), 1.95-2.02 (m, 1H), 1.31-1.85 (m, 10H).LC-MS: (M+H)+=449.2; HPLC purity=99.50%.

Example 1771-[3-(6-fluoro-1H-indol-3-yl)-4-methylpentanoyl]decahydroquinoline-4-carboxylicacid (peak-1) (177)

Synthesis of Compound (177)

Compound (177) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 10.87 (brs,1H), 7.48-7.53 (dd, 1H), 7.04-7.07 (m, 2H), 6.75-6.82 (m, 1H), 3.75-3.96(m, 2H), 3.17-3.24 (q, 2H), 2.67-2.69 (d, 2H), 2.23-2.30 (m, 1H),1.94-2.02 (m, 2H), 1.01-1.84 (m, 10H), 0.86-0.88 (d, 3H), 0.76-0.78 (d,3H). LC-MS: (M+H)+=415.2; HPLC purity=99.75%.

Example 1781-[3-(6-fluoro-1H-indol-3-yl)-4-methylpentanoyl]decahydroquinoline-4-carboxylicacid (peak-2) (178)

Synthesis of Compound (178)

Compound (178) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 8.81 (brs, 0.5H),8.45 (brs, 0.5H), 7.43-7.47 (dd, 1H), 6.84-6.90 (m, 1H), 6.79 (brs, 1H),6.70-6.76 (m, 1H), 4.35-4.50 (m, 1H), 3.45-3.53 (m, 1H), 3.02-3.15 (m,2H), 2.63-2.77 (m, 2H), 2.00-2.10 (m, 1H), 1.75-1.95 (m, 2H), 1.23-1.65(m, 10H), 0.94-0.96 (d, 3H), 0.78-0.80 (d, 3H). LC-MS: (M+H)+=415.2;HPLC purity=88.97%.

Example 1791-[3-(4-fluoro-1H-Indol-3-yl)-4-methylpentanoyl]decahydroquinoline-4-carboxylicacid (179)

Synthesis of Compound (179)

Compound (179) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 8.44 (brs, 0.5H),8.37 (brs, 1H), 6.88-7.05 (m, 3H), 6.62-6.70 (m, 1H), 4.37-4.50 (m, 1H),3.61 (t, 1H), 3.51-3.58 (m, 1H), 3.10-3.20 (m, 1H), 2.60-2.80 (m, 2H),2.34-2.45 (m, 1H), 1.99-2.04 (m, 1H), 1.79-1.87 (m, 1H), 1.15-1.80 (m,10H), 0.93-0.95 (d, 3H), 0.70-0.72 (d, 3H). LC-MS: (M+H)+=415.3; HPLCpurity=96.54%.

Example 1801-[4-methyl-3-(4-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pentanoyl]decahydroquinoline-4-carboxylicacid (180)

Synthesis of Compound (180)

Compound (180) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 11.71 (brs,0.5H), 11.32 (brs, 0.5H), 7.88-8.01 (m, 1H), 7.07 (s, 1H), 6.81-6.84 (m,1H), 3.92-3.94 (m, 1H), 3.73-3.75 (m, 1H), 3.45-3.50 (m, 1H), 2.86 (s,2H), 2.84 (s, 1H), 2.45-2.70 (m, 4H), 1.95-2.10 (m, 2H), 1.12-1.75 (m,10H), 0.95-1.05 (m, 6H). LC-MS: (M+H)+=412.3; HPLC purity=97.39%.

Example 1811-[3-(1H-benzotriazol-1-yl)-3-phenylpropanoyl]decahydroquinoline-4-carboxylicacid (peak-1) (181)

Synthesis of Compound (181)

Compound (181) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 7.67-7.73 (m,3H), 7.45-7.50 (m, 1H), 7.37-7.42 (m, 4H), 7.21-7.28 (dd, 1H), 7.08-7.13(d, 1H), 4.55-4.65 (m, 1H), 4.25-4.41 (m, 1H), 4.00-4.13 (m,1H)<3.02-3.09 (m, 1H), 3.02-3.09 (m, 1H), 2.72-2.79 (m, 1H), 2.27-2.32(m, 1H), 1.30-2.15 (m, 10H). LC-MS: (M+H)+=433.2; HPLC purity=98.45%.

Example 1821-[3-(1H-benzotriazol-1-yl)-3-phenylpropanoyl]decahydroquinoline-4-carboxylicacid (Peak-2) (182)

Synthesis of Compound (182)

Compound (182) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): 12.36 (brs, 1H),7.69-7.71 (d, 2H), 7.36-7.48 (m, 7H), 7.19-7.24 (d, 1H), 4.26-4.30 (m,1H), 4.11-4.15 (m, 1H), 3.52-3.59 (m, 2H), 2.39-2.45 (m, 2H), 2.25-2.28(m, 1H), 1.35-2.16 (m, 10H). LC-MS: (M+H)+=433.2; HPLC purity=97.16%.

Example 1831-[4-methyl-3-(4-methyl-1H-benzotriazol-1-yl)pentanoyl]decahydroquinoline-4-carboxylicacid (183)

Synthesis of Compound (183)

Compound (183) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 7.38-7.41 (d,1H), 7.25-7.30 (t, 1H), 7.00-7.03 (d, 1H), 5.02-5.05 (m, 1H), 3.95-4.10(m, 1H), 3.46-3.68 (m, 2H), 2.84-2.90 (m, 1H), 2.75 (s, 3H), 2.21-2.39(m, 4H), 1.25-1.95 (m, 10H), 0.96-0.98 (d, 3H), 0.75-0.77 (d, 3H).LC-MS: (M+H)+=413.2; HPLC purity=95.52%.

Example 1841-[3-(4-chloro-1H-indol-3-yl)-3-(thiophen-2-yl)propanoyl]decahydroquinoline-4-carboxylicacid (184)

Synthesis of Compound (184)

Compound (184) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 8.36 (br s, 1H),7.16-7.21 (m, 2H), 7.11-7.14 (d, 1H), 7.06-7.09 (m, 1H), 6.95-6.97 (m,1H), 6.83-6.78 (m, 2H), 5.58-5.64 (m, 1H), 4.40-4.60 (m, 1H), 3.60-3.65(m, 1H), 3.34-3.42 (M, 1H), 2.99-3.19 (m, 1H), 2.43-2.71 (m, 1H),2.12-2.15 (m, 1H), 1.23-1.84 (m, 11H). LC-MS: (M+H)+=471.2; HPLCpurity=98.02%.

Example 1851-[3-(6-chloro-1H-indol-3-yl)-4-methylpentanoyl]decahydroquinoline-4-carboxylicacid (185)

Synthesis of Compound (185)

Compound (185) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 10.94 (br s,1H), 7.52-7.55 (d, 1H), 7.33 (s, 1H), 7.13 (s, 1H), 6.93-6.96 (d, 1H),3.78-3.97 (m, 1H), 3.34-3.41 (m, 1H), 3.16-3.22 (m, 2H), 2.68-2.70 (m,2H), 2.29-2.33 (m, 1H), 1.06-2.02 (m, 12H), 0.86-0.88 (d, 3H), 0.75-0.77(d, 3H). LC-MS: (M+H)+=431.3; HPLC purity=96.39%.

Example 1861-[3-(4-fluoro-1H-indol-3-yl)-3-phenylpropanoyl]decahydroquinoline-6-carboxylicacid (186)

Synthesis of Compound (186)

Compound (186) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): 12.07 (br s, 1H),11.18 (brs, 1H), 7.33-7.38 (m, 1H), 7.18-7.29 (m, 4H), 7.08-7.15 (m,2H), 6.93-7.00 (m, 1H), 6.55-6.64 (m, 1H), 4.78-4.85 (m, 1H), 4.18-4.35(m, 1H), 3.74-4.00 (m, 1H), 2.93-3.19 (m, 2H), 2.20-2.25 (m, 2H),1.25-1.82 (m, 11H). LC-MS: (M+H)+=449.3; HPLC purity=98.98%.

Example 1871-[3-(4-chloro-1H-indol-3-yl)pentanoyl]decahydroquinoline-4-carboxylicacid (187)

Synthesis of Compound (187)

Compound (187) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 8.31 (brs 1H),7.16-7.18 (m, 1H), 6.97-7.01 (m, 3H), 3.65-3.87 (m, 2H), 3.39-3.53 (m,1H), 2.44-2.73 (m, 4H0, 1.23-1.85 (m, 13H), 0.81-0.86 (t, 3H). LC-MS:(M+H)+=417.2; HPLC purity=90.53%.

Example 1881-[3-(4-fluoro-1H-indol-3-yl)-3-phenylpropanoyl]decahydroquinoline-5-carboxylicacid (188)

Synthesis of Compound (188)

Compound (188) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): 12.26 (br s, 1H),11.18 (br s, 1H), 7.32-7.35 (m, 1H), 7.09-7.27 (m, 6H), 6.93-7.00 (m,1H), 6.58-6.64 (m, 1H), 4.79-4.86 (m, 1H), 4.04-4.41 (m, 1H), 3.93-4.05(m, 1H), 3.75-3.79 (m, 1H), 2.95-3.17 (m, 2H), 2.71-2.75 (m, 1H),1.25-1.89 (m, 11H). LC-MS: (M+H)+=449.2; HPLC purity=94.73%.

Example 189(1-[3-(4-cyclopropyl-1H-indol-3-yl)butanoyl]decahydroquinolin-4-yl)aceticacid (189)

Synthesis of Compound (189)

Compound (189) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 7.99 (br s, 1H),7.09-7.12 (d, 1H), 6.97-7.01 (m, 2H), 6.66-6.68 (d, 1H), 4.45-4.53 (m,0.5H), 4.10-4.15 (m, 1H), 3.50-3.64 (m, 1H), 3.05-3.07 (m, 0.5H),2.67-2.83 (m, 2H), 2.19-2.50 (m, 4H), 1.40-1.96 (m, 12H), 1.36-1.38 (d,3H), 0.89-0.93 (m, 2H), 0.82-0.85 (m, 2H). LC-MS: (M+H)+=423.2; HPLCpurity=95.52%.

Example 1901-[3-(4-cyclopropyl-1H-Indol-3-yl)butanoyl]decahydroquinoline-5-carboxylicacid (190)

Synthesis of ethyl 3-(4-bromo-1H-indol-3-yl)butanoate (intermediate-94)

Intermediate-94 was synthesized by following the procedure used to makeIntermediate-2 (Scheme-1).

Synthesis of ethyl 3-(4-cyclopropyl-1H-indol-3-yl)butanoate(intermediate-95)

A 250 mL RB flask fitted with magnetic stirrer was charged withIntermediate-94 (15.95 g, 51.47 mmol), cyclopropylboronic acid (8.8 g,102.9 mmol), cesium carbonate (33.45 g, 102.9 mmol), in a mixture ofdioxane and water (100 mL: 20 ML). Then purged with N₂ gas and addedPdCl₂(dppf) (4.2 g, 5.1 mmol). Resulting solution was stirred at 100° C.for 13 h. After completion of the reaction (reaction monitored by TLC),reaction solution was filtered through celite. Filtrate diluted withwater and extracted with EtOAc and concentrated to give crude material,which is purified by silica gel column chromatography eluting withPetroleum ether (60-80) and ethyl acetate as eluent. The product(intermediate-95) was obtained as a brown liquid (12.5 g).

Synthesis of 3-(4-cyclopropyl-1H-indol-3-yl)butanoic acid(intermediate-96)

Intermediate-96 was synthesized by following the procedure used to makeIntermediate-3 (Scheme-1).

Synthesis of methyl quinoline-5-carboxylate (intermediate-97)

A 500 mL RB flask fitted with magnetic stirrer was charged with StartingMaterial-32 (60 g, 435 mmol), Starting material-33 (168 g, 1824 mmol),3-nitrobenzoic acid (30 g, 179 mmol) in 90 mL of conc.H₂SO₄. Thenreaction mixture was heated at 150° C. for 7 h. After reaction cooled toRT and added MeOH (600 mL) and refluxed for 12 hours. Then cooled to 0°C. quenched with ice and concentrated. Crude reaction mixture wasbasified with NaHCO₃, extracted with DCM and concentrated. Resultedcrude material was purified by silica gel column chromatography elutingwith Petroleum ether (60-80), ethyl acetate and 0.5% of triethylamine aseluent. The product (intermediate-97) was obtained as a brown liquid (21g).

Synthesis of quinoline-5-carboxylic acid (intermediate-98)

To a stirred solution of Intermediate-97 (21 g, 112 mmol) in a mixtureof THF: MeOH (25 mL: 200 mL) was added LiOH (10.75 g, 448 mmol) in water(25 mL) at 0 qC. Resulted reaction mixture was stirred at roomtemperature for 3 hours. After reaction (monitored by TLC), it wasconcentrated and acidified (PH=5) with 1N. HCl. Resisted precipitate wasfiltered and dried to give product Intermediate-98 (19 g).

Synthesis of decahydroquinoline-5-carboxylic acid (intermediate-99)

Intermediate-99 was synthesized by following the procedure used to makeIntermediate-18 (Scheme-13).

Synthesis of methyl decahydroquinoline-5-carboxylate (intermediate-100)

A 250 mL RB flask fitted with magnetic stirrer was charged withIntermediate-99 (5.4 g, 29.5 mmol) in 50 mL MeOH. To thisthionylchloride (10 mL) was slowly added at 0° C. Resulted reactionmixture was stirred at room temperature for 12 hours. After reaction(Monitered by LC-MS), it was concentrated followed by azetroped withwith tolune to give product Intermediate-100 as white solid (4.4 g).

Synthesis of Compound (190)

Compound (190) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 7.94 (br s, 1H),7.10-7.12 (m, 1H), 6.96-7.00 (m, 2H), 6.65-6.69 (m, 1H), 4.68-4.70 (m,0.5H), 4.44-4.48 (m, 0.5H), 4.14-4.17 (m, 1H), 3.57-3.63 (m, 1H),2.70-2.94 (m, 2H), 2.41-2.55 (m, 3H), 2.12-2.15 (m, 1H), 1.44-1.77 (m,8H), 1.35-1.37 (d, 3H), 1.30-1.35 (m, 2H), 0.91-0.93 (m, 2H), 0.77-0.80(m, 2H). LC-MS: (M+H)+=409.2; HPLC purity=97.56%.

Example 1911-[3-(4-cyclopropyl-1H-Indol-3-yl)butanoyl]decahydroquinoline-6-carboxylicacid (191)

Synthesis of Compound (191)

Compound (191) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 12.11 (br s,1H), 10.80 (br s, 1H), 7.16-7.19 (m, 1H), 7.12-7.14 (d, 1H), 6.88-6.93(t, 1H), 6.55-6.58 (d, 1H), 4.05-4.10 (m, 1H), 3.70-3.73 (m, 1H),2.90-3.01 (m, 1H), 2.61-2.70 (m, 2H), 2.30-2.39 (m, 2H), 2.25-2.28 (m,1H), 1.31-2.06 (m, 11H), 1.27-1.29 (d, 3H), 0.89-0.91 (m, 2H), 0.72-0.73(m, 2H). LC-MS: (M+H)+=409.2; HPLC purity=93.25%.

Example 1921-{3-[4-(thiophen-2-yl)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (192)

Synthesis of Compound (192)

Compound (192) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 8.30 (br s, 1H),7.37-7.40 (d, 1H), 7.29-7.32 (m, 1H), 7.18-7.20 (d, 1H), 7.08-7.15 (m,4H), 3.22-3.46 (m, 2H), 2.71-2.93 (m, 1H), 2.39-2.57 (m, 2H), 2.10-2.25(m, 2H), 1.42-1.94 (m, 11H), 0.85-0.88 (d, 3H). LC-MS: (M+H)+=451.1;HPLC purity=99.67%.

Example 1931-[3-(4-chloro-1H-indol-3-yl)butanoyl]decahydroquinoline-5-carboxylicacid (HS_A_643) (193)

Synthesis of Compound (193)

Compound (193) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 12.15 (br s,1H), 11.18 (brs, 1H), 7.28-7.31 (m, 2H), 7.01-6.98 (m, 2H), 4.47-4.49(m, 0.5H), 4.29-4.33 (m, 0.5H), 3.72-3.95 (m, 2H), 2.62-3.02 (m, 4H),1.30-1.94 (m, 11H), 1.25-1.27 (d, 3H). LC-MS: (M+H)+=403.1; HPLCpurity=98.12%.

Example 1941-[3-(4-cyclopropyl-1H-indol-3-yl)butanoyl]decahydroquinoline-4-carboxylicacid (194)

Synthesis of Compound (194)

Compound (194) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 7.95 (br s, 1H),7.10-7.13 (d, 1H), 6.96-7.02 (m, 2H), 6.66-6.68 (d, 1H), 4.17-4.20 (m,2H), 3.46-3.49 (m, 1H), 2.80-2.88 (m, 1H), 2.53-2.60 (m, 2H), 2.41-2.48(m, 2H), 1.45-1.98 (m, 11H), 1.36-1.38 (d, 3H), 0.92-0.95 (m, 2H),0.74-0.81 (m, 2H). LC-MS: (M+H)+=409.2; HPLC purity=92.83%.

Example 1951-[3-(4-cyclopropyl-1H-indol-3-yl)butanoyl]decahydroquinoline-5-carboxylicacid (peak-1) (195)

Synthesis of 3-(4-cyclopropyl-1H-indol-3-yl)butanoic acid(intermediate-101, Peak-1)

Intermediate-101, peak-1 was synthesized by following the procedure usedto make Intermediate-90, peak-1 (Scheme-54). 1H NMR (300 MHz, DMSO-d6):δ 12.01 (br s, 1H), 10.83 (br s, 1H), 7.12-7.15 (m, 2H) m 6.89-6.94 (t,1H), 6.58-6.61 (d, 1H), 3.99-4.03 (m, 1H), 2.71-2.78 (dd, 1H), 2.34-2.42(m, 2H), 1.30-1.32 (d, 3H), 0.92-0.94 (m, 2H), 0.72-0.74 (m, 2H). LC-MS:(M+H)+=244.1; HPLC purity=96.90%; Chiral RT=7.91 min [chiral pak IA,mobile phase hexane:i-PrOH:DCM (8.5:1.0:0.5)]; [α]_(D) ²³=+10.62° (c0.032, MeOH).

Synthesis of methyl1-[3-(4-cyclopropyl-1H-indol-3-yl)butanoyl]decahydroquinoline-5-carboxylate(intermediate-102, Peak-1)

Intermediate-102, peak-1 was synthesized by following the procedure usedto make Compound-1 (Scheme-2).

Synthesis of Compound (195)

Compound (195) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 8.04 (br s, 1H),7.08-7.11 (d, 1H), 6.95-6.98 (m, 2H), 6.68 (s, 1H), 4.44-4.68 (m, 1H),4.16 (br s, 1H), 3.39-3.59 (m, 1H), 2.66-2.93 (m, 2H), 2.14-2.51 (m,3H), 1.38-1.85 (m, 11H), 1.30-0.132 (d, 3H), 0.91-0.93 (m, 2H),0.70-0.72 (m, 2H). LC-MS: (M+H)+=409.2; HPLC purity=96.52%.

Example 1961-[3-(4-cyclopropyl-1H-indol-3-yl)butanoyl]decahydroquinoline-5-carboxylicacid (196)

Synthesis of 3-(4-cyclopropyl-1H-indol-3-yl)butanoic acid(intermediate-103, Peak-2)

Intermediate-103, peak-2 was synthesized by following the procedure usedto make Intermediate-90, peak-1 (Scheme-54). 1H NMR (300 MHz, DMSO-d6):δ 12.01 (br s, 1H), 10.83 (br s, 1H), 7.12-7.15 (m, 2H) m 6.89-6.94 (t,1H), 6.58-6.61 (d, 1H), 3.99-4.03 (m, 1H), 2.71-2.78 (dd, 1H), 2.34-2.42(m, 2H), 1.30-1.32 (d, 3H), 0.92-0.94 (m, 2H), 0.72-0.74 (m, 2H). LC-MS:(M+H)+=244.1; HPLC purity=89.91%; Chiral RT=9.15 min [chiral pak IA,mobile phase hexane:i-PrOH:DCM (8.5:1.0:0.5)]; [α]_(D) ²³=−6.04° (c0.033, MeOH)

Synthesis of methyl1-[3-(4-cyclopropyl-1H-indol-3-yl)butanoyl]decahydroquinoline-5-carboxylate(intermediate-104, Peak-2)

Intermediate-104, peak-2 was synthesized by following the procedure usedto make Compound-1 (Scheme-2).

Synthesis of Compound (196)

Compound (196) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 8.08 (br s, 1H),7.08-7.10 (d, 1H), 6.94-7.00 (m, 2H), 6.65-6.67 (m, 1H), 4.44-4.68 (m,1H), 4.15 (br s, 1H), 3.38-3.64 (m, 1H), 2.71-2.92 (m, 2H), 2.13-2.54(m, 3H), 1.45-1.78 (m, 11H), 1.40-1.43 (d, 3H), 0.90-0.93 (m, 2H),0.74-0.77 (m, 2H). LC-MS: (M+H)+=409.2; HPLC purity=96.11%.

Example 1971-[3-(4-cyano-1H-indol-3-yl)butanoyl]decahydroquinoline-5-carboxylicacid (197)

Synthesis of Compound (197)

Compound (197) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 12.13 (br s,1H), 11.48 (br s, 1H), 7.67-7.70 (d, 1H), 7.46-7.48 (m, 2H), 7.17-7.22(t, 1H), 4.45-4.49 (m, 0.5H), 4.25-4.30 (0.5H), 3.74-3.85 (m, 3H),2.91-3.00 (m, 1H), 2.69-2.86 (m, 2H), 1.30-1.98 (m, 14H). LC-MS:(M+H)+=394.2; HPLC purity=99.0%.

Example 1981-[3-(4-cyclopropyl-1H-indol-3-yl)butanoyl]decahydroquinoline-5-carboxylicacid (HS_A_648, peak-la) (198)

Synthesis of Compound (198)

Mixture of isomers 195 was separated by using chiral columnchromatography to give Compound 198. 1H NMR (300 MHz, CDCl3): δ 7.92 (brs, 1H), 7.10-7.13 (d, 1H), 6.97-7.02 (m, 2H), 6.67-6.69 (m, 1H),4.67-4.72 (m, 0.5H), 4.45-4.48 (m, 0.5H), 4.16-4.18 (m, 1H), 3.00-3.62(m, 1H), 2.69-2.96 (m, 2H), 2.37-2.48 (m, 2H), 2.13-2.24 (m, 1H),1.37-1.92 (m, 11H), 1.33-1.35 (d, 3H), 0.92-0.95 (m, 2H), 0.83-0.88 (M,2H). LC-MS: (M+H)+=409.2; HPLC purity=99.39%; Chiral RT=12.44 min[Column: Chiral Pak IC; mobile phase: hexane: IPA:DCM (8:1:1)].

Example 1991-[3-(4-cyclopropyl-1H-indol-3-yl)butanoyl]decahydroquinoline-5-carboxylicacid (peak-1 b) (199)

Synthesis of Compound (199)

Mixture of isomers 195 was separated by using chiral columnchromatography to give Compound 199. 1H NMR (300 MHz, DMSO-d6): δ 12.11(br s, 1H), 10.80 (br s, 1H), 7.12-7.18 (m, 2H), 6.88-6.93 (t, 1H),6.55-6.58 (d, 1H), 4.49-4.52 (m, 0.5H), 4.31-4.35 (m, 0.5H), 3.91-4.04(m, 2H), 3.70-3.74 (m, 1H), 2.86-2.98 (m, 1H), 2.67-2.74 (m, 2H),2.37-2.39 (m, 1H), 1.47-2.00 (M, 11H), 1.27-1.30 (d, 3H), 0.85-0.91 (m,2H), 0.68-0.74 (m, 2H). LC-MS: (M+H)+=409.2; HPLC purity=99.31%; ChiralRT=14.93 min [Column: Chiral Pak IC; mobile phase: hexane: IPA:DCM(8:1:1)]. [α]_(D) ²⁴=+111.84° (c 0.001, MeOH).

Example 2001-[3-(4-cyclopropyl-1H-Indol-3-yl)butanoyl]decahydroquinoline-5-carboxylicacid (peak-1c) (200)

Synthesis of Compound (200)

Mixture of isomers 195 was separated by using chiral columnchromatography to give Compound 200. 1H NMR (300 MHz, DMSO-d6): δ 12.23(br s, 1H), 10.80 (br s, 1H), 7.11-7.16 (m, 2H), 6.88-6.93 (t, 1H),6.55-6.57 (d, 1H), 4.54-4.56 (m, 0.5H), 4.30-4.34 (m, 0.5H), 3.89-4.06(m, 2H), 3.70-3.73 (m, 1H), 2.92-3.00 (m, 1H), 2.66-2.72 (m, 2H),2.26-2.29 (m, 1H), 1.35-1.98 (m, 11H), 1.28-1.31 (d, 3H), 0.87-0.91 (m,2H), 0.70-0.74 (m, 2H). LC-MS: (M+H)+=409.2; HPLC purity=94.22%; ChiralRT=14.61 min [Column: Chiral Pak IC; mobile phase: hexane: IPA:DCM(8:1:1)].

Example 2011-{3-[4-(propan-2-yloxy)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (201)

Synthesis of Compound (201)

Compound (201) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 12.0 (br s,1H), 10.67 (br s, 1H), 6.83-6.92 (m, 3H), 6.40-6.43 (d, 1H), 4.69-4.72(m, 1H), 4.53-4.55 (m, 0.5H), 4.06-4.09 (m, 0.5H), 3.58-3.75 (m, 3H),2.63-2.98 (m, 2H), 2.18-2.22 (m, 1H), 1.45-1.98 (m, 11H), 1.27-1.31 (m,9H). LC-MS: (M+H)+=427.2; HPLC purity=95.46%.

Example 2021-{3-[4-(octahydroquinolin-1(2H)-yl)-4-oxobutan-2-yl]-1H-indol-4-yl}piperidine-4-carboxylicacid (202)

Synthesis of Intermediate-105

Intermediate-105 was synthesized by following the procedure used to makeCompound (1) (Scheme2).

Synthesis of Intermediate-106

To a stirred solution of Intermediates-105 (0.35 g, 1.09 mmol) in dryTHF (4 mL), NaH (0.052 g, 2.1 mmol) was added at 0° C. and stirred for10 minutes. To the stirred solution tosyl chloride (0.27 g, 1.4 mmol)was added and stirred for 30 minutes at room temperature. Aftercompletion of the reaction, the reaction mixture was quenched with H₂O,extracted with EtOAc to give crude material which was purified by usingSilica-gel column chromatography eluting with mixture of hexanes: EtOActo give Intermediate-106 (260 mg).

Synthesis of Intermediate-107

To a stirred solution of Intermediate-106 (0.26 g, 0.46 mmol) in dioxane(4 mL), methyl isonipecotate (0.10 mL, 0.69 mmol) and cesium carbonate(0.46 g, 1.39 mmol) were added. The resulted reaction mixture was purgedwith argon gas and Pd₂(dba)₃ (0.085 g, 0.009 mmol), BINAP (0.015 g,0.023 mmol) were added, then heated at 90° C. for 12 hours. Aftercompletion of the reaction, the reaction mixture was filtered throughcelite and concentrated to give crude material which was purified byusing Silica-gel column chromatography eluting with mixture of hexanes:EtOAc to give Intermediate-107 (150 mg).

Synthesis of Intermediate-108

To a stirred solution of magnesium (0.3 g, 12.3 mmol) in MeOH (18 mL),Intermediate-107 (0.15 g, 0.29 mol) and ammonium chloride (0.12 g, 2.1mmol) were added, and stirred for 2 hours at room temperature. Aftercompletion of the reaction, the reaction mixture was quenched withsaturated NH₄CI solution, extracted with EtOAc and concentrated to givecrude material which was purified by using Silica-gel columnchromatography eluting with mixture of hexanes: EtOAc to giveIntermediate-108 (50 mg).

Synthesis of Compound (202)

To a stirred solution of Intermediate-108 (0.05 g, 0.10 mmol) in THF:MeOH (2 mL, 1:1), aqueous NaOH (0.021 g, 0.53 mmol) was added andstirred at room temperature for 8 hours. After completion of thereaction, the reaction mixture was concentrated to give crude product,which was taken in H₂O, acidified with 10% aqueous KHSO₄ (PH=5),extracted with EtOAc, concentrated, and purified by using Silica-gelcolumn chromatography eluting with mixture of hexanes: EtOAc to giveCompound-202 (10 mg) as brown solid. 1H NMR (300 MHz, CDCl3): δ 7.95 (brs, 1H), 7.03-7.06 (m, 2H), 6.91-6.94 (m, 1H), 6.72-6.75 (m, 1H),4.46-4.61 (m, 1H), 3.80-3.84 (m, 0.5H), 3.58-3.60 (m, 0.5H), 3.29-3.31(m, 1H), 3.15-3.18 (m, 1H), 2.85-2.92 (m, 2H), 2.45-2.48 (m, 3H),2.10-2.15 (m, 2H), 1.30-1.94 (m, 20H). LC-MS: (M+H)+=452.2; HPLCpurity=96.62%.

Example 2031-[3-(4-chloro-5-methyl-1H-indol-3-yl)butanoyl]decahydroquinoline-5-carboxylicacid (203)

Synthesis of Compound (203)

Compound (203) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 11.10 (br s,1H), 7.18-7.23 (m, 2H), 6.97-7.00 (d, 1H), 4.46-4.55 (m, 1H), 4.20-4.34(m, 1H), 3.91-3.95 (m, 1H), 3.75-3.79 (m, 2H), 2.36 (s, 3H), 2.27-2.30(m, 2H), 1.30-1.90 (m, 14H). LC-MS: (M+H)+=417.1; HPLC purity=99.11%.

Example 2041-[3-(4-cyclopropyl-1-methyl-1H-indol-3-yl)butanoyl]decahydroquinoline-5-carboxylicacid (204)

Synthesis of Compound (204)

Compound (204) was synthesized by following the procedure used to makeCompound (27) (Scheme 26). 1H NMR (300 MHz, CDCl3): δ 7.10-7.12 (m, 2H),6.88-6.91 (d, 1H), 6.72-6.75 (m, 1H), 4.77-4.82 (m, 0.5H), 4.54-4.58 (m,0.5H), 4.23-4.25 (m, 1H), 3.72 (s, 3H), 3.68-3.70 (m, 1H), 2.74-2.92 (m,1H), 2.54-2.62 (m, 1H), 2.46-2.49 (m, 2H), 2.20-2.23 (m, 1H), 1.30-1.90(m, 14H0, 0.98-1.01 (m, 2H0, 0.83-0.86 (m, 2H). LC-MS: (M+H)+=423.2;HPLC purity=98.91%.

Example 2051-[3-(4-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)butanoyl]decahydroquinoline-5-carboxylicacid (205)

Synthesis of Compound (205)

Compound (205) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 11.01 (br s, 1H),7.91-8.00 (m, 1H), 7.04 (s, 1H), 6.46-6.59 (m, 1H), 4.51-4.63 (m, 1H),4.38-4.42 (m, 1H), 3.98-4.06 (m, 2H), 3.44-3.47 (0.5H), 3.15-3.19 (m,0.5H), 2.84-2.95 (m, 1H), 2.37-2.54 (m, 2H), 1.55-1.85 (m, 6H),1.45-1.47 (d, 3H), 1.30-1.40 (m, 5H), 0.94-0.97 (m, 2H0, 0.78-0.83 (m,2H). LC-MS: (M+H)+=410.2; HPLC purity=98.14%.

Example 2061-[3-(4-chloro-1H-indol-3-yl)-3-(thiophen-2-yl)propanoyl]decahydroquinoline-5-carboxylicacid (206)

Synthesis of Compound (206)

Compound (206) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 12.13 (br s,1H), 11.31 (br s, 1H), 7.40-7.45 (m, 1H), 7.31-7.33 (d, 1H), 7.20-7.22(m, 1H), 7.00-7.05 (t, 1H), 6.93-6.96 (d, 1H), 6.78-6.87 (m, 2H),5.54-5.56 (m, 1H), 4.43-4.45 (m, 0.5H), 4.19-4.26 (m, 0.5H), 4.01-4.03(M, 1H), 3.78-3.82 (m, 1H), 3.02-3.11 (m, 2H), 2.40-2.45 (m, 1H),1.31-1.88 (m, 11H). LC-MS: (M+H)+=471.1; HPLC purity=97.94%.

Example 2071-[3-(1,4-dimethyl-1H-indol-3-yl)butanoyl]decahydroquinoline-5-carboxylicacid (207)

Synthesis of Compound (207)

Compound (207) was synthesized by following the procedure used to makeCompound (27) (Scheme 26). 1H NMR (300 MHz, CDCl3): δ 7.05-7.12 (m, 2H),6.80-6.89 (m, 2H), 4.73-4.77 (m, 0.5H), 4.52-4.56 (m, 0.5H), 3.91-3.95(m, 1H), 3.71 (s, 3H), 3.60-3.63 (m, 1H), 2.86-3.06 (m, 1H), 2.72 (s,3H), 2.41-2.57 (m, 2H), 2.21-2.24 (m, 1H), 1.49-1.90 (m, 11H), 1.39-1.41(d, 3H). LC-MS: (M+H)+=397.2; HPLC purity=98.36%.

Example 2081-{3-[1-methyl-4-(propan-2-yloxy)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (208)

Synthesis of Compound (208)

Compound (208) was synthesized by following the procedure used to makeCompound (27) (Scheme 26). 1H NMR (300 MHz, DMSO-d6: δ 12.01 (br s, 1H),6.84-7.02 (m, 3H), 6.46-6.48 (m, 1H), 4.70-4.72 (m, 1H), 4.45-4.50 (m,0.5H), 4.30-4.33 (m, 0.5H), 3.70-3.72 (m, 1H), 3.64 (s, 3H), 3.51-3.53(m, 1H), 2.66-3.05 (m, 3H), 2.23-2.39 (m, 1H), 1.45-1.98 (m, 11H),1.30-1.42 (m, 9H). LC-MS: (M+H)+=441.2; HPLC purity=99.01%.

Example 2091-[3-(4-chloro-1-methyl-1H-indol-3-yl)butanoyl]decahydroquinoline-5-carboxylicacid (209)

Synthesis of Compound (209)

Compound (209) was synthesized by following the procedure used to makeCompound (27) (Scheme 26). 1H NMR (300 MHz, CDCl3): δ 7.09-7.11 (m, 1H),6.97-7.05 (m, 2H), 6.85-6.91 (m, 1H), 4.664.68 (m, 0.5H), 4.47-4.49 (m,0.5H), 3.66 (s, 3H), 2.69-3.05 (m, 2H), 2.36-2.57 (m, 1H), 2.16-2.24 (m,1H), 1.45-1.90 (m, 11H0, 1.33-1.35 (d, 3H). LC-MS: (M+H)+=417.1; HPLCpurity=98.82%.

Example 2101-[3-(4-cyclopropyl-1-ethyl-1H-indol-3-yl)butanoyl]decahydroquinoline-5-carboxylicacid (210)

Synthesis of Compound (210)

Compound (210) was synthesized by following the procedure used to makeCompound (27) (Scheme 26). 1H NMR (300 MHz, CDCl3): δ 6.98-7.09 (m, 2H0,6.87-6.91 (m, 1H), 6.64-6.66 (d, 1H), 4.68-4.70 (m, 0.5H), 4.48-4.51 (m,0.5H), 4.14-4.16 (m, 1H), 4.00-4.07 (q, 2H), 3.57-3.65 (m, 1H),2.68-2.98 (m, 2H), 2.39-2.58 (m, 2H), 2.15-2.27 (m, 1H), 1.40-1.97 (m,11H), 1.34-1.36 (d, 3H), 0.88-0.94 (m, 2H), 0.75-0.81 (m, 5H). LC-MS:(M+H)+=437.2; HPLC purity=98.31%.

Example 2111-{3-[4-(propan-2-yl)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (211)

Synthesis of Compound (211)

Compound (211) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 7.99 (br s, 1H),7.15-7.18 (m, 2H), 7.01-7.05 (m, 2H), 4.74-4.77 (m, 0.5H0, 4.53-4.56 (m,0.5H0, 3.85-3.88 (m, 1H), 3.62-3-66 (m, 2H), 2.44-3.04 (m, 3H),2.21-2.23 (m, 1H), 1.46-1.95 (m, 11H), 1.41-1.43 (d, 3H), 1.34-1.36 (d,6H). LC-MS: (M+H)+=411.2; HPLC purity=93.44%.

Example 2121-[3-(4-cyclopropyl-1-methyl-1H-indol-3-yl)butanoyl]decahydroquinoline-5-carboxylicacid (peak-1) (212)

Synthesis of Compound (212)

Mixture of isomers of Compound (204) was separated by using chiralcolumn chromatography to give compound 212. 1H NMR (300 MHz, CDCl3): δ7.03-7.05 (m, 2H), 6.81 (s, 1H), 6.65-6.68 (m, 1H), 4.19-4.23 (m, 1H),4.09-4.10 (m, 1H), 3.66 (s, 3H), 3.36-3.40 (m, 1H), 3.00-3.03 (m, 1H),2.70-2.84 (m, 1H), 2.38-2.45 (m, 2H), 2.21-2.26 (m, 1H), 1.45-1.95 (m,11H), 1.33-1.36 (d, 3H), 0.92-0.95 (m, 2H), 0.76-0.79 (m, 2H). LC-MS:(M+H)+=423.2; HPLC purity=99.14%; Chiral RT=19.99 min [Column: ChiralPak IC; mobile phase: hexane: IPA:DCM (8.5:0.5:1.0)].

Example 2131-[3-(4-cyclopropyl-1-methyl-1H-indol-3-yl)butanoyl]decahydroquinoline-5-carboxylicacid (peak-2) (213)

Synthesis of Compound (213)

Mixture of isomers of Compound (204) was separated by using chiralcolumn chromatography to give compound 213. 1H NMR (300 MHz, CDCl3): δ7.03-7.05 (m, 2H), 6.82-6.85 (d, 1H), 6.65-6.68 (m, 1H), 4.67-4.70 (m,0.5H), 4.44-4.49 (m, 0.5H), 4.15-4.16 (m, 1H), 3.65 (s, 3H), 3.42-3.46(m, 1H), 2.79-2.95 (m, 2H), 2.68-2.70 (m, 1H), 2.56-2.59 (m, 1H),2.39-2.43 (m, 1H), 1.38-1.82 (m, 11H), 1.31-1.34 (d, 3H), 0.92-0.94 (m,2H), 0.76-0.80 (m, 2H). LC-MS: (M+H)+=423.2; HPLC purity=94.30%; ChiralRT=27.35 min [Column: Chiral Pak IC; mobile phase: hexane: IPA:DCM(8.5:0.5:1.0)].

Example 2141-[3-(4-cyclopropyl-1-methyl-1H-indol-3-yl)butanoyl]decahydroquinoline-5-carboxylicacid (peak-3) (214)

Synthesis of Compound (214)

Mixture of isomers of Compound (204) was separated by using chiralcolumn chromatography to give compound 214. 1H NMR (300 MHz, CDCl3): δ7.03-7.05 (m, 2H), 6.82-6.85 (d, 1H), 6.65-6.68 (m, 1H), 4.67-4.70 (m,0.5H), 4.46-4.49 (m, 0.5H), 4.11-4.14 (m, 1H), 3.65 (s, 3H), 3.42-3.46(m, 1H), 2.79-2.95 (m, 2H), 2.68-2.70 (m, 1H), 2.56-2.59 (m, 1H),2.39-2.43 (m, 1H), 1.38-1.82 (m, 11H), 1.31-1.34 (d, 3H), 0.92-0.94 (m,2H), 0.76-0.80 (m, 2H). LC-MS: (M+H)+=423.2; HPLC purity=98.00%; ChiralRT=30.61 min [Column: Chiral Pak IC; mobile phase: hexane: IPA:DCM(8.5:0.5:1.0)].

Example 2151-{3-[4-(furan-2-yl)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (215)

Synthesis of Compound (215)

Compound (215) was synthesized by following the procedure used to make(105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 12.14 (br s, 1H), 11.08(br s, 1H), 7.63-7.65 (m, 1H), 7.39-7.41 (d, 1H), 7.25 (s, 1H),7.06-7.11 (t, 1H), 6.94-7.03 (m, 1H), 6.52-6.54 (m, 2H), 4.45-4.47 (m,0.5H), 4.24-4.28 (m, 0.5H), 3.66-3.74 (m, 1H), 3.46-3.49 (m, 1H),2.82-2.90 (m, 1H), 2.57-2.72 (m, 1H), 2.07-0.31 (m, 1H), 2.07-2.10 (m,1H), 1.25-1.85 (m, 11H), 1.04-1.09 (d, 3H). LC-MS: (M+H)+=435.2; HPLCpurity=93.62%.

Example 2161-{3-[4-(furan-2-yl)-1-methyl-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (216)

Synthesis of Compound (216)

Compound (216) was synthesized by following the procedure used to make(105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 7.43-7.48 (m, 1H),7.24-7.27 (m, 1H), 7.09-7.16 (m, 2H), 6.91 (s, 1H), 6.40-6.42 (m, 2H),4.56-4.60 (m, 0.5H), 4.39-4.42 (m, 0.5H), 3.70 (s, 3H), 3.50-3.53 (m,1H), 3.22-3.37 (m, 2H), 2.65-2.81 (m, 1H), 2.37-2.46 (m, 1H), 1.99-2.18(m, 1H), 1.37-1.83 (m, 11H), 1.32-1.35 (d, 3H). LC-MS: (M+H)+=449.2;HPLC purity=97.01%.

Example 2171-[3-(4-cyclopropyl-1H-indol-3-yl)butanoyl]decahydroquinoline-6-carboxylicacid (217)

Synthesis of Compound (217)

Compound (217) was synthesized by following the procedure used to makeCompound (195) (Scheme 59). 1H NMR (300 MHz, CDCl3): δ 7.95 (br s, 1H),7.10-7.12 (d, 1H), 6.99-7.01 (d, 1H), 6.96 (s, 1H), 6.65-6.68 (d, 1H),4.62-4.63 (m, 0.5H), 4.44-4.46 (m, 0.5H), 4.16-4.18 (m, 1H), 3.56-3.58(m, 1H), 2.77-2.86 (m, 1H), 2.69-2.71 (m, 1H), 2.42-2.45 (m, 1H),2.18-2.24 (m, 1H), 1.35-1.75 (m, 11H), 1.30-1.33 (d, 3H), 0.92-0.95 (m,2H), 0.78-0.81 (m, 2H). LC-MS: (M+H)+=409.2; HPLC purity=96.63%.

Example 2181-[3-(4-chloro-1H-indol-3-yl)-3-(thiophen-2-yl)propanoyl]decahydroquinoline-5-carboxylicacid (peak-1) (218)

Synthesis of Compound (218)

Compound (218) was synthesized by following the procedure used to makeCompound (195) (Scheme 58). 1H NMR (300 MHz, DMSO-d6): δ 12.14 (br s,1H), 11.31 (br s, 1H), 7.40-7.45 (m, 1H), 7.31-7.33 (d, 1H), 7.20-7.22(m, 1H), 7.00-7.05 (m, 1H), 6.89-6.96 (m, 1H), 6.78-6.86 (m, 2H),5.48-5.55 (m, 1H), 4.42-4.44 (m, 0.5H), 4.22-4.26 (m, 0.5H), 4.00-4.04(m, 0.5H), 3.78-3.83 (m, 0.5H), 2.95-3.16 (m, 2H), 2.45-2.55 (m, 2H),1.32-1.92 (m, 11H). LC-MS: (M+H)+=471.1; HPLC purity=99.98%.

Example 2191-[3-(4-chloro-1H-indol-3-yl)-3-(thiophen-2-yl)propanoyl]decahydroquinoline-5-carboxylicacid (peak-2) (219)

Synthesis of Compound (219)

Compound (219) was synthesized by following the procedure used to makeCompound (196) (Scheme 59). 1H NMR (300 MHz, DMSO-d6): δ 12.15 (br s,1H), 11.34 (br s, 1H), 7.41-7.45 (m, 1H), 7.31-7.33 (d, 1H), 7.22-7.24(m, 1H), 7.00-7.05 (m, 2H), 6.94-6.96 (d, 1H), 6.86-6.89 (m, 1H),5.56-5.58 (m, 1H), 4.41-4.51 (m, 0.5H), 4.21-4.23 (m, 0.5H), 4.00-4.04(m, 1H), 3.78-3.82 (m, 1H), 2.95-3.11 (m, 2H), 2.08-2.15 (m, 1H),1.33-1.80 (m, 11H). LC-MS: (M+H)+=471.1; HPLC purity=91.48%.

Example 2201-[3-(4-cyclopropyl-5-fluoro-1H-indol-3-yl)butanoyl]decahydroquinoline-5-carboxylicacid (220)

Synthesis of Compound (220)

Compound (220) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 8.02 (br s, 1H),7.08-7.11 (m, 2H), 6.80-6.87 (t, 1H), 4.72-4.74 (m, 0.5H), 4.50-4.54 (m,0.5H), 4.18-4.20 (m, 1H), 3.65-3.68 (m, 1H), 2.80-3.07 (m, 1H),2.51-2.64 (m, 2H), 2.01-2.05 (m, 1H), 1.45-1.86 (11H), 1.39-1.42 (d,3H), 1.06-1.08 (m, 2H), 0.88-0.92 (m, 2H). LC-MS: (M+H)+=427.2; HPLCpurity=99.0%.

Example 2211-{3-[4-(furan-2-yl)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (221)

Synthesis of Compound (221)

Compound (221) was synthesized by following the procedure used to makeCompound (195) (Scheme 58). 1H NMR (300 MHz, CDCl3): δ 8.20 (br s, 1H),7.51-7.55 (m, 1H), 7.39-7.41 (m, 1H), 7.14-7.19 (m, 3H), 6.48-6.50 (m,2H), 4.66-4.69 (m, 0.5H), 4.43-4.45 (m, 0.5H), 4.11-4.32 (m, 1H),3.53-3.63 (m, 1H), 2.80-2.85 (m, 1H), 2.53-2.62 (m, 1H), 2.28-2.35 (m,2H), 1.40-1.80 (m, 11H), 1.28-1.31 (d, 3H). LC-MS: (M+H)+=435.2; HPLCpurity=98.74%.

Example 2221-{3-[4-(furan-2-yl)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (222)

Synthesis of Compound (222)

Compound (222) was synthesized by following the procedure used to makeCompound (196) (Scheme 59). 1H NMR (300 MHz, CDCl3): δ 8.27 (br s, 1H),7.51-7.56 (m, 1H) m 7.38-7.41 (m, 1H), 7.23-7.28 (m, 1H), 7.13-7.17 (m,3H), 6.48-6.50 (d, 1H), 4.63-4.67 (m, 0.5H), 4.46-4.49 (m, 0.5H),3.51-3.64 (m, 1H), 3.37-3.40 (m, 1H), 2.80-2.88 (m, 1H), 2.49-2.62 (m,1H), 2.16-2.29 (m, 2H), 1.40-1.86 (m, 11H), 1.36-1.38 (d, 3H). LC-MS:(M+H)+=435.2; HPLC purity=99.83%.

Example 2231-{3-[4-(furan-2-yl)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (223)

Synthesis of Compound (223)

Mixture of isomers of Compound (221) separated by preparative chiralchromatography to give Compound (223). 1H NMR (300 MHz, CD3OD): δ7.57-7.60 (d, 1H), 7.37-7.42 (t, 1H), 7.17 (br s, 1H), 7.05-7.11 (m,2H), 6.52-6.53 (m, 1H), 6.46-6.47 (m, 1H), 4.28-4.31 (d, 1H), 3.50-3.63(m, 2H), 2.48-2.54 (m, 2H), 2.20-2.36 (m, 1H), 2.02-2.06 (m, 1H),1.28-1.80 (m, 11H), 1.21-1.23 (d, 3H). LC-MS: (M+H)+=435.2; HPLCpurity=100%. Chiral RT=19.31 min [Column: Chiral Pak IC; mobile phase:hexane: IPA:DCM (8.5:1:0.5)].

Example 2241-{3-[4-(furan-2-yl)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (224)

Synthesis of Compound (224)

Mixture of isomers of Compound (221) separated by preparative chiralchromatography to give Compound (224). 1H NMR (300 MHz, CDCl3): δ 8.14(br s, 1H), 7.44-7.49 (d, 1H), 7.32-7.34 (d, 1H), 7.08-7.12 (m, 3H),6.41-6.44 (d, 2H), 4.56-4.61 (m, 0.5H), 4.39-4.43 (m, 0.5H), 4.20 (4.25(dd, 0.5H), 4.01-4.10 (m, 0.5H), 3.47-3.59 (m, 1H), 3.30-3.34 (m, 1H),2.73-2.81 (m, 1H), 2.42-2.52 (m, 1H), 2.28-2.30 (m, 1H), 1.48-1.80 (m,11H), 1.35-1.37 (d, 3H). LC-MS: (M+H)+=435.2; HPLC purity=96.72%. ChiralRT=23.19 min [Column: Chiral Pak IC; mobile phase: hexane: IPA:DCM(8.5:1:0.5)].

Example 2251-[3-(4-fluoro-1H-indol-3-yl)-3-(4-fluorophenyl)propanoyl]decahydroquinoline-4-carboxylicacid (peak-1) (225)

Synthesis of Compound (225)

Compound (225) was synthesized by following the procedure used to makeCompound (195) (Scheme 58). 1H NMR (300 MHz, DMSO-d6): δ 12.23 (br s,1H), 11.19 (br s, 1H), 7.25-7.36 (m, 3H), 7.13-7.16 (d, 1H), 7.03-7.06(d, 1H), 6.93-6.97 (m, 2H), 6.59-6.65 (dd, 1H), 4.84 (br s, 1H),3.88-3.94 (m, 1H), 3.30-3.32 (m, 1H), 2.94-3.21 (m, 2H), 2.38-2.40 (m,1H), 1.40-1.90 (m, 11H). LC-MS: (M+H)+=467.1; HPLC purity=95.38%.

Example 2261-[3-(4-fluoro-1H-indol-3-yl)-3-(4-fluorophenyl)propanoyl]decahydroquinoline-4-carboxylicacid (peak-2) (226)

Synthesis of Compound (226)

Compound (226) was synthesized by following the procedure used to makeCompound (196) (Scheme 59). 1H NMR (300 MHz, DMSO-d6): δ 12.24 (br s,1H), 11.20 (br s, 1H), 7.36-7.37 (m, 1H), 7.25-7.29 (t, 2H), 7.13-7.16(d, 1H), 7.03-7.06 (d, 1H), 6.94-7.00 (m, 2H), 6.59-6.66 (dd, 1H), 4.84(br s, 1H), 3.88-3.90 (m, 1H), 3.29-3.32 (m, 1H), 2.93-3.21 (m, 2H),2.38-2.42 (m, 2H), 1.28-1.91 (m, 11H). LC-MS: (M+H)+=467.1; HPLCpurity=100%.

Example 2271-{3-[4-(furan-2-yl)-1H-indol-3-yl]butanoyl}decahydroquinoline-4-carboxylicacid (227)

Synthesis of Compound (227)

Compound (227) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 8.39 (br s, 1H),7.51-7.53 (m, 1H), 7.37-7.39 (m, 1H), 7.13-7.20 (m, 4H), 6.48 (s, 1H),3.55-3.58 (m, 1H), 3.37-3.42 (m, 1H), 2.39-2.58 (m, 3H), 2.23-2.29 (m,2H), 1.45-1.87 (m, 11H), 1.41-1.43 (d, 3H). LC-MS: (M+H)+=435.1; HPLCpurity=98.43%.

Example 2281-[3-(4-chloro-1H-indol-3-yl)butanoyl]decahydroquinoline-6-carboxylicacid (228)

Synthesis of Compound (228)

Compound (228) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 8.19 (br s, 1H),7.21-7.24 (m, 1H), 7.03-7.10 (m, 3H), 4.27-4.68 (m, 1H), 4.11-4.17 (m,1H), 3.68-3.71 (m, 1H), 2.80-3.02 (m, 1H), 2.40-2.53 (m, 2H), 2.28-2.33(m, 1H), 1.50-1.89 (m, 11H), 1.45-1.47 (d, 3H). LC-MS: (M+H)+=403.3;HPLC purity=94.02%.

Example 2291-{3-[4-(furan-2-yl)-1H-indol-3-yl]butanoyl}decahydroquinoline-6-carboxylicacid (229)

Synthesis of Compound (229)

Compound (229) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 8.19 (br s, 1H),7.50-7.52 (m, 1H), 7.39-7.41 (m, 1H), 7.18-7.20 (m, 2H), 7.14 (s, 1H),6.48-6.49 (d, 2H), 4.27-4.32 (dd, 0.5H), 4.11-4.17 (d, 0.5H), 3.57-3.59(m, 1H), 3.39-3.41 (m, 1H), 2.75-2.79 (m, 1H), 2.22-2.38 (m, 3H),1.47-1.87 (m, 14H). LC-MS: (M+H)+=435.2; HPLC purity=98.67%.

Example 2301-[3-(4-cyclopropyl-1H-indol-3-yl)butanoyl]-2-methyldecahydroquinolin-5-carboxylicacid (230)

Synthesis of Compound (230)

Compound (230) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 12.16 (br s,1H), 10.81 (br s, 1H), 7.17 (s, 1H), 7.13-7.15 (d, 1H), 6.88-6.94 (t,1H), 6.55-6.58 (t, 1H), 4.58-4.62 (t, 0.5H), 4.41-4.45 (m, 0.5H),3.99-4.11 (m, 1H), 3.81-3.85 (m, 1H), 2.58-2.93 (m, 2H), 2.31-2.43 (m,2H), 1.33-1.99 (m, 11H), 1.27-1.30 (d, 3H), 1.06-1.08 (d, 3H), 0.90-0.96(m, 2H), 0.65-0.72 (m, 2H). LC-MS: (M+H)+=423.4; HPLC purity=98.0%.

Example 2311-{3-[4-(furan-2-yl)-1H-indol-3-yl]butanoyl}-2-methyldecahydroquinoline-5-carboxylicacid (231)

Synthesis of Compound (231)

Compound (231) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 12.11 (br s, 1H),11.09 (br s, 1H), 7.61-7.64 (m, 1H), 7.39-7.42 (d, 1H), 7.23-7.26 (d,1H), 7.06-7.12 (t, 1H), 7.02-7.03 (m, 1H), 6.51-6.53 (m, 2H), 4.49-4.51(m, 0.5H), 4.33-4.45 (m, 0.5H), 3.96-3.98 (m, 1H), 2.65-2.73 (m, 2H),2.16-2.28 (m, 2H), 1.37-1.94 (m, 11H), 1.15-1.18 (d, 3H), 1.02-1.05 (d,3H). LC-MS: (M+H)+=449.2; HPLC purity=98.27%.

Example 2322-methyl-1-{3-[4-(thiophen-2-yl)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (232)

Synthesis of Compound (232)

Compound (232) was synthesized by following the procedure used to makeCompound (195) (Scheme 58). 1H NMR (300 MHz, CDCl3): δ 8.23 (br s, 1H),7.317.41 (m, 2H), 7.12-7.22 (m, 5H), 4.62-4.64 (m, 0.5H), 4.47-4.51 (m,0.5H), 3.71-3.77 (m, 1H), 3.42-3.54 (m, 1H), 2.55-2.64 (m, 1H),2.27-2.35 (m, 1H), 2.05-2.12 (m, 1H), 1.25-1.75 (m, 11H), 1.14-1.16 (d,3H), 1.09-1.11 (d, 3H). LC-MS: (M+H)+=465.4; HPLC purity=96.26%.

Example 2332-methyl-1-{3-[4-(thiophen-2-yl)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (233)

Synthesis of Compound (233)

Compound (233) was synthesized by following the procedure used to makeCompound (196) (Scheme 59). 1H NMR (300 MHz, CDCl3): δ 8.47 (br s, 1H),7.21-7.29 (m, 2H), 7.00-7.11 (m, 5H), 4.56-4.57 (m, 0.5H), 4.41-4.43 (m,0.5H), 3.63-3.68 (m, 1H), 3.42-3.44 (m, 1H), 2.51-2.59 (m, 1H),2.25-2.27 (m, 1H), 2.02-2.10 (m, 1H), 1.34-1.68 (m, 11H), 1.00-1.03 (d,3H), 0.98-1.00 (d, 3H). LC-MS: (M+H)+=465.4; HPLC purity=97.31%.

Example 2341-[3-(4-chloro-1H-indol-3-yl)butanoyl]-2-methyldecahydroquinoline-5-carboxylicacid (234)

Synthesis of Compound (234)

Compound (234) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 12.14 (br s,1H), 11.20 (br s, 1H), 7.25-7.32 (m, 2H), 6.96-7.02 (m, 2H), 4.58-4.60(m, 0.5H), 4.41-4.43 (m, 0.5H), 3.99-4.01 (m, 1H), 2.72-2.93 (m, 2H),2.25-2.27 (m, 1H), 1.92-1.97 (m, 1H), 1.30-1.72 (m, 11H), 1.15-1.17 (d,3H), 1.07-1.09 (d, 3H). LC-MS: (M+H)+=417.1; HPLC purity=97.11%.

Example 2351-[3-(4-chloro-1H-indol-3-yl)butanoyl]octahydroquinolin-4(1H)-one (235)

Synthesis of Compound (235)

Compound (235) was synthesized by following the procedure used to makeCompound (26) (Scheme 25). 1H NMR (300 MHz, CDCl3): δ 8.18 (br s, 1H),7.16-7.18 (m, 1H), 7.04-7.07 (m, 1H), 7.01-7.03 (d, 2H), 4.91-4.95 (m,0.5H), 4.62-4.68 (m, 0.5H), 4.08-4.11 (m, 1H), 3.86-3.98 (m, 1H),3.31-3.46 (m, 0.5H), 2.83-2.91 (m, 1H), 2.48-2.70 (m, 1H), 2.11-2.23 (m,3H), 1.53-1.70 (m, 8H), 1.46-1.48 (d, 3H), 1.41-1.43 (d, 3H). LC-MS:(M+H)+=373.3; HPLC purity=97.62%.

Example 2361-{3-[4-(5-methylfuran-2-yl)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (236)

Synthesis of Compound (236)

Compound (236) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 8.19 (br s, 1H),7.28-7.32 (m, 1H), 7.05-7.16 (m, 3H), 6.29-6.33 (m, 1H), 5.98-6.00 (m,1H), 4.58-4.60 (m, 0.5H), 4.37-4.42 (m, 0.5H), 3.49-3.62 (m, 1H),3.28-3.31 (m, 1H), 2.43-2.55 (m, 2H), 2.30 (s, 3H), 2.05-2.07 (m, 1H),1.97-2.05 (m, 1H), 1.24-1.80 (m, 11H), 1.18-1.20 (d, 3H). LC-MS:(M+H)+=449.2; HPLC purity=98.32%.

Example 2371-[3-(4-cyclopropyl-1H-indol-3-yl)butanoyl]-5-methyldecahydroquinoline-5-carboxylicacid (237)

Synthesis of Compound (237)

Compound (237) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 12.20 (br s,1H), 10.79 (br s, 1H), 7.12-7.15 (d, 2H), 6.88-6.92 (t, 1H), 6.55-6.58(d, 1H), 4.01-4.03 (m, 1H), 3.69-3.87 (m, 1H), 2.90-2.95 (m, 1H),2.65-2.78 (m, 2H), 2.35-2.41 (m, 2H), 1.49-1.98 (m, 10H), 1.28 (s, 3H),1.24-1.26 (d, 3H). LC-MS: (M+H)+=423.2; HPLC purity=91.85%.

Example 2381-{3-[4-(pyridin-2-yl)-1H-Indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (238)

Synthesis of Compound (238)

Compound (238) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 12.15 (br s,1H), 11.06 (br s, 1H), 8.59 (br s, 1H), 7.82-7.87 (t, 1H), 7.51-7.53 (d,1H), 7.41-7.44 (d, 1H), 7.33-7.36 (m, 1H), 7.23 (s, 1H), 7.10-7.15 (t,1H), 6.90-6.92 (d, 1H), 4.37-4.40 (m, 0.5H), 4.16-4.20 (m, 0.5H),3.64-3.69 (m, 1H), 3.10-3.14 (m, 1H), 2.69-2.80 (m, 2H), 2.30-2.35 (m,1H), 2.14-2.19 (m, 1H), 1.45-2.00 (m, 11H), 1.33-1.37 (d, 3H). LC-MS:(M+H)+=446.2; HPLC purity=96.69%.

Example 2391-{3-[4-(3-methyl-1,2-oxazol-5-yl)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (239)

Synthesis of Compound (239)

Compound (239) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 8.28 (br s, 1H),7.48-7.51 (d, 1H), 7.13-7.16 (m, 2H), 7.09 (s, 1H), 6.34 (s, 1H),4.46-4.50 (m, 0.5H), 4.20-4.25 (dd, 1H), 4.04-4.08 (dd, 1H), 3.84-3.86(m, 0.5H), 3.39-3.45 (m, 1H), 2.52-2.60 (m, 1H), 2.37 (s, 3H), 2.24-2.30(m, 1H), 2.12-2.17 (m, 1H), 1.35-1.90 (m, 14H). LC-MS: (M+H)+=450.2;HPLC purity=99.79%.

Example 2403-(4-cyclopropyl-1H-indol-3-yl)-1-[5-(1H-tetrazol-5-yl)octahydroquinolin-1(2H)-yl]butan-1-one(240)

Synthesis of Compound (240)

To a stirred solution of Intermediate-109 (30 mg, 0.077 mmol) in DMF (2mL), NaN3 (25 mg, 0.38 mmol) and ammonium chloride (15 mg, 0.22 mmol)were added. Resulted reaction mixture was heated at 110° C. for 48hours. After completion of the reaction (monitored by TLC), the reactionmixture was quenched with water and was extracted with ethyl acetate(3×10 mL). The combined organic layer was concentrated to obtain a crudeproduct. The resulted crude product was purified by preparative HPLC togive Compound (240) (2.5 mg) as brown gummy material. 1H NMR (300 MHz,CDCl3): δ 8.03 (br s, 1H), 7.08-7.11 (m, 1H), 6.97-7.04 (m, 2H),6.63-6.70 (m, 1H), 5.20-5.27 (m, 1H), 4.08-4.24 (m, 2H), 3.52-3.58 (m,1H), 2.77-2.97 (m, 2H), 2.21-2.30 (m, 2H), 1.45-1.90 (m, 11H), 1.37-1.40(d, 3H), 0.70-0.90 (m, 4H). LC-MS: (M−H)+=431.3; HPLC purity=91.69%.

Example 2411-[3-(4-cyclopropyl-1-methoxy-1H-indol-3-yl)butanoyl]decahydroquinoline-5-carboxylicacid (241)

Synthesis of Compound (241)

Compound (241) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 7.10 (s, 1H),7.02-7.07 (m, 2H), 6.65-6.68 (d, 1H), 4.20-4.25 (m, 1H), 4.04-4.10 (m,2H), 3.98 (s, 3H), 3.52-3.65 (m, 1H), 2.61-2.82 (m, 1H), 2.38-2.47 (m,2H), 2.21-2.24 (m, 1H), 0.7-1.90 (m, 18H). LC-MS: (M+H)+=439.3; HPLCpurity=92.8%.

Example 2421-{3-[4-cyclopropyl-1-(methoxymethyl)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (242)

Synthesis of Compound (242)

Compound (242) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 7.23 (s, 1H),7.02-7.07 (t, 1H), 6.94-6.97 (d, 1H), 6.70-6.72 (d, 1H), 5.31 (s, 2H),4.62-4.69 (m, 0.5H), 4.49-4.52 (m, 0.5H), 4.17-4.25 (m, 1H), 4.04-4.10(m, 1H), 3.52-3.62 (m, 1H), 3.18 (s, 3H), 2.75-2.81 (m, 1H), 2.39-2.43(m, 2H), 2.15-2.30 (m, 1H), 1.39-1.80 (m, 11H), 1.32-1.35 (d, 3H),0.94-0.96 (m, 2H), 0.73-0.77 (m, 2H). LC-MS: (M−H)+=451.2; HPLCpurity=92.13%.

Example 2431-{3-[4-(4-fluorophenyl)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (243)

Synthesis of Compound (243)

Compound (243) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 8.25 (br s, 1H),7.36-7.46 (m, 3H), 7.18-7.22 (t, 1H), 7.06-7.13 (m, 3H), 6.90-6.93 (d,1H), 4.55-4.59 (m, 0.5H), 4.36-4.39 (m, 0.5H), 3.45-3.49 (m, 1H),3.11-3.15 (m, 1H), 2.52-2.77 (m, 2H), 2.31-2.40 (dd, 1H), 2.07-2.16 (m,2H), 1.36-1.96 (m, 10H), 1.13-1.15 (d, 3H). LC-MS: (M−H)+=463.3; HPLCpurity=98.0%.

Example 2441-{3-[4-(1-methyl-1H-pyrrol-2-yl)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (244)

Synthesis of Compound (244)

Compound (244) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). LC-MS: (M−H)+=448.4; HPLC purity=84.68%.

Example 2451-{3-[4-(5-fluorofuran-2-yl)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (245)

Synthesis of Intermediate-110

To a stirred solution of Starting Material-34 (1.0 g, 5.26 mmol) inwater (5 mL) sodium bicarbonate (1.06 g, 12.6 mmol) was added at roomtemperature and stirred for 30 min. To this n-hexane (5 mL) followed byselectfluor (2.23 g, 6.31 mmol) was added at 10° C. and stirred for 2hours at same temperature. After reaction hexane layer was separated anddried over anhydrous MgSO₄ to give crude intermediate-110 hexanesolution, which was taken for next step without any purification.

Synthesis of Intermediate-111

To a stirred solution of Intermediate-110 hexanes solution (0.863 g,5.26 mmol) in ether (5 mL) was added 2.5 M n-BuLi (2.52 mL, 6.31 mmol)at −78° C. and stirred for 20 minutes. To this tributyltin chloride(1.56 mL, 5.78 mmol) was added and stirred for 10 min at −78° C., thenrt for 12 h. After reaction quenched with aqueous 1N NaOH solution andextracted with EtOAc and concentrated to give crude materialIntermediate-111 (0.95 g) as brown liquid.

Synthesis of Intermediate-112

To a stirred solution of Intermediate-110 (0.050 g, 0.16 mmol), andIntermediate-111 (0.060 g, 0.16 mmol) in toluene purged with argon gasfor 15 minutes, then added PdCl₂ (Dppf) catalyst (0.013 g, 0.016 mmol).Then reaction was carried out under micro wave for 30 min at 130° C.After reaction quenched with water and extracted with EtOAc andconcentrated to give crude material, which was further purified bysilica gel column chromatography eluting with hexanes: EtOAc to give0.035 g of Intermediate-112 as brown liquid).

Synthesis of Intermediate-113

Intermediate-113 was synthesized by following the procedure used to makeIntermediate-3 (Scheme 1).

Synthesis of Intermediate-114

Intermediate-114 was synthesized by following the procedure used to makeCompound-1 (Scheme 2).

Synthesis of Compound (245)

Compound (245) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 8.24 (br s, 1H),7.40-7.42 (m, 1H), 7.15-7.21 (m, 3H), 6.37-6.39 (m, 1H), 5.51-5.54 (m,1H), 4.66-4.70 (m, 0.5H), 4.48-4.52 (m, 0.5H), 3.60-3.61 (m, 1H),3.47-3.51 (m, 1H), 2.91-2.99 (m, 1H), 2.59-2.76 (m, 2H), 2.31-2.39 (m,1H), 2.20-2.23 (m, 1H), 1.41-1.86 (m, 10H), 1.31-1.34 (d, 3H). LC-MS:(M−H)+=453.2; HPLC purity=97.87%.

Example 2465-{3-[4-(octahydroquinolin-1(2H)-yl)-4-oxobutan-2-yl]-1H-indol-4-yl}furan-2-carboxylicacid (246)

Synthesis of Intermediate-116

To a stirred solution of Intermediate-115 (0.2 g, 0.49 mmol) in dioxane(5 mL), bis(pinacolato)diboron (0.25 g, 0.99 mmol), and KOAc (0.145 g,1.48 mmol) were added, and then the reaction solution was purged withargon gas. To the reaction mixture PdCl₂(dppf) (0.040 g, 0.049 mmol) wasadded and heated at 100° C. for 12 hours. After completion of thereaction, the reaction mixture was diluted with H₂O, extracted withEtOAc and concentrated to give crude product. The crude product waspurified using Silica-gel column chromatography eluting with mixture ofhexanes: EtOAc to give Intermediate-116 (100 mg) as brown gummymaterial.

Synthesis of Compound (246)

To a stirred solution of Intermediate-116 (0.1 g, 0.22 mmol) in dioxane:H₂O (5 mL, 8:2), 2-bromofuroic acid (0.084 g, 0.44 mmol) and Cs₂CO₃(0.28 g, 0.88 mmol) were added, and then reaction solution was purgedwith argon gas. To the reaction mixture PdCl₂(dppf) (0.018 g, 0.022mmol) was added and heated at 100° C. for 12 hours. After completion ofreaction, the reaction mixture was diluted with H₂O, extracted withEtOAc and concentrated to give crude product. The crude product waspurified using Silica-gel column chromatography eluting with mixture ofhexanes: EtOAc to give Compound-246 (12 mg) as white solid. 1H NMR (300MHz, CDCl3): δ 8.59 (br s, 1H), 7.42-7.45 (m, 1H), 7.34-7.37 (m, 1H),7.19-7.25 (m, 3H), 6.62-6.64 (m, 1H), 4.53-4.56 (m, 0.5H), 4.42-4.47 (m,0.5H), 3.61-3.65 (m, 1H), 3.49-3.53 (m, 1H), 2.80-2.84 (m, 1H),2.61-2.63 (m, 1H), 2.29-2.31 (m, 1H), 1.47-1.87 (m, 13H), 1.41-1.44 (d,3H). LC-MS: (M−H)+=435.3; HPLC purity=99.33%.

Example 247N-({1-[3-(4-cyclopropyl-1H-indol-3-yl)butanoyl]decahydroquinolin-5-yl}carbonyl)glycine(247)

Synthesis of Compound (247)

Compound (247) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 12.30 (brs,1H), 10.79 (br s, 1H), 8.02-8.04 (m, 1H), 7.12-7.15 (m, 2H), 6.88-6.93(t, 1H), 6.55-6.59 (m, 1H), 4.49-4.52 (m, 0.5H), 4.31-4.33 (m, 0.5H),4.02-4.05 (m, 1H), 3.68-3.70 (m, 2H), 3.10-3.13 (m, 1H), 2.93-2.98 (m,1H), 2.62-2.78 (m, 2H), 2.31-2.35 (m, 2H), 1.90-1.95 (m, 1H), 1.37-1.75(m, 10H), 1.31-1.34 (d, 3H), 0.84-0.88 (m, 2H), 0.72-0.76 (m, 2H).LC-MS: (M−H)+=466.4; HPLC purity=94.3%.

Example 2481-{3-[4-(5-fluorofuran-2-yl)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (248)

Synthesis of Intermediate-117

To a stirred solution of Intermediate-100 (14.5 g, 62.0 mmol) in DCM(250 mL), 50 mL of TEA (31.39 g, 310 mmol) was added followed by benzylchloroformate (15.87 g, 93.1 mmol) at 0° C. Then it was stirred at roomtemperature for 12 hours. After completion of the reaction the reactionmixture was quenched with water and extracted with DCM. The combinedorganic layers were concentrated to give crude material, which wasfurther purified by using silica gel column chromatography eluting withhexanes: EtOAc to give 20 g of Intermediate-117 as pate brown liquid.

Separation of Intermediate-118:

Mixture of isomers of Intermediate 117 (20 g) was separated by usingPreparative Reverse HPLC to give 6.4 g of Intermediate-118: HPLC:[Column: Phenomenex Luna C-18, Mobile phase: 0.1% Formic acid in H2O andMeCN (1:1), RT=15.40 min].

Synthesis of Intermediate-121

A stirred solution of Intermediate-118 (6.4 g, 19.33 mmol) in MeOH (70mL) was purged with N₂ gas, and then 10% Pd—C (1.2 g, 10% w/w) wasadded. The resulted reaction mixture was stirred under hydrogenatmosphere for 12 hours. After completion of the reaction, the reactionmixture was filtered through the celite and concentrated to giveIntermediate-121 (3.79 g) as white solid.

Synthesis of Intermediate-122, Peak-1

Intermediate-122, peak-1 was synthesized by following the procedure usedto make Intermediate-90 (Peak-1) (Scheme 54).

Synthesis of Intermediate-123, Peak-1

Intermediate-123, peak-1 was synthesized by following the procedure usedto make Intermediate-91 (Peak-1) (Scheme 54).

Synthesis of Compound (248)

Compound (248) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CD3OD): δ 7.33-7.37 (m,1H), 7.12-7.14 (d, 1H), 7.01-7.05 (t, 1H), 6.94-6.97 (m, 1H), 6.30-6.33(m, 1H), 5.53-5.56 (m, 1H), 4.46-4.55 (m, 0.5H), 4.23-4.28 (m, 0.5H),3.43-3.57 (m, 2H), 2.83-2.92 (m, 1H), 2.46-2.73 (m, 2H), 2.17-2.36 (m,1H), 1.97-2.06 (m, 1H), 1.49-1.78 (m, 10H), 1.37-1.40 (d, 3H). LC-MS:(M−H)+=453.3; HPLC purity=93.80%.

Example 2491-{3-[4-(5-fluorofuran-2-yl)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (249)

Synthesis of Intermediate-124, Peak-2

Intermediate-124, peak-2 was synthesized by following the procedure usedto make Intermediate-92 (Peak-2) (Scheme 55).

Synthesis of Intermediate-125, Peak-2

Intermediate-125, peak-2 was synthesized by following the procedure usedto make Intermediate-93 (Peak-2) (Scheme 55).

Synthesis of Compound (249)

Compound (249) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 8.24 (br s, 1H),7.40-7.42 (m, 1H), 7.13-7.21 (m, 3H), 6.35-6.38 (m, 1H), 5.50-5.54 (m,1H), 4.66-4.70 (m, 0.5H), 4.48-4.52 (0.5H), 3.60-3.62 (m, 1H), 3.47-3.51(m, 1H), 2.91-2.99 (m, 1H), 2.60-2.73 (m, 2H), 2.32-2.39 (m, 1H),2.25-2.28 (m, 1H), 1.48-1.87 (m, 10H), 1.41-1.43 (d, 3H). LC-MS:(M−H)+=453.3; HPLC purity=98.07%.

Example 2501-{3-[4-(5-fluorofuran-2-yl)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (250)

Synthesis of Compound (250)

Mixture of isomers of Compound (248) separated by using chiral columnchromatography to give Compound (250). 1H NMR (300 MHz, CD3OD): δ7.39-7.45 (t, 1H), 7.20 (s, 1H), 7.01-7.15 (m, 2H), 6.39-6.41 (m, 1H),5.60-5.66 (m, 1H), 4.53-4.57 (d, 0.5H), 4.30-4.34 (d, 0.5H), 3.50-3.59(m, 2H), 2.86-2.99 (m, 1H), 2.65-2.70 (m, 1H), 2.52-2.60 (m, 2H),2.00-2.21 (m, 1H), 1.46-1.73 (m, 10H), 1.37-1.40 (d, 3H). LC-MS:(M−H)+=453.3; HPLC purity=98.29%; chiral purity=94.75% [column:Chiralpak IC; mobile phase: hexane: IPA: DCM (8.5:1.0:0.5); RT=10.88min].

Example 2511-{3-[4-(5-fluorofuran-2-yl)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (251)

Synthesis of Compound (251)

Mixture of isomers of Compound (248) separated by using chiral columnchromatography to give Compound (251). 1H NMR (300 MHz, CDCl3): δ 8.32(br s, 1H), 7.32-7.35 (d, 1H), 7.05-7.13 (m, 3H), 6.29-6.32 (m, 1H),5.43-5.46 (m, 1H), 4.58-4.62 (m, 0.5H), 4.39-4.44 (m, 0.5H), 3.52-3.56(m, 2H), 2.83-2.91 (m, 1H), 2.61-2.70 m, 1H), 2.46-2.51 (m, 1H),2.25-2.34 (m, 1H), 2.07-2.18 (m, 1H), 1.45-1.79 (m, 10H), 1.37-1.40 (d,3H). LC-MS: (M−H)+=453.4; HPLC purity=96.81%. chiral purity=99.52%[column: Chiralpak IC; mobile phase: hexane: IPA: DCM (8.5:1.0:0.5);RT=13.71 min].

Example 2521-[3-(2-cyano-4-cyclopropyl-1H-indol-3-yl)butanoyl]decahydroquinoline-5-carboxylicacid (252)

Synthesis of Compound (252)

Compound (252) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 8.75 (br s, 1H),7.13-7.22 (m, 2H), 6.90-6.92 (d, 1H), 4.76-4.81 (m, 1H), 4.67-4.71 (m,0.5H), 4.40-4.53 (m, 0.5H), 3.78-4.01 (m, 1H), 3.01-3.27 (m, 1H),2.85-2.97 (m, 1H), 2.50-2.57 (m, 2H), 2.22 (2.36 (m, 1H), 2.12-2.18 (m,1H), 1.52-1.85 (m, 10H), 1.46-1.49 (d, 3H), 1.01-1.04 (m, 2H), 0.84-0.87(m, 2H). LC-MS: (M−H)+=434.3; HPLC purity=97.78%.

Example 2531-{3-[4-(4-fluorophenyl)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (253)

Synthesis of Compound (253)

Compound (253) was synthesized by following the procedure used to makeCompound (159, peak-1) (Scheme 53-54). 1H NMR (300 MHz, CDCl3): δ 8.27(br s, 1H), 7.42-7.46 (m, 2H), 7.36-7.39 (d, 1H), 7.14-7.20 (t, 1H),7.08-7.14 (m, 3H), 6.90-6.97 (m, 1H), 4.55-4.59 (m, 0.5H), 4.37-4.39 (m,0.5H), 3.06-3.32 (m, 2H), 2.73-2.82 (m, 1H), 2.59-2.64 (m, 1H),2.41-2.48 (m, 1H), 2.32-2.38 (m, 1H), 2.10-2.15 (m, 1H), 1.39-1.93 (m,10H), 1.13-1.15 (d, 3H). LC-MS: (M−H)+=463.3; HPLC purity=95.23%,

Example 2541-{3-[4-(4-fluorophenyl)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (254)

Synthesis of Compound (254)

Compound (254) was synthesized by following the procedure used to makeCompound (160, peak-2) (Scheme 53 and 55). 1H NMR (300 MHz, CDCl3): δ8.30 (br s, 1H), 7.42-7.46 (m, 2H), 7.36-7.39 (d, 1H), 7.17-7.22 (t,1H), 7.07-7.14 (m, 3H), 6.90-6.97 (m, 1H), 4.55-4.59 (m, 0.5H),4.37-4.39 (m, 0.5H), 3.11-3.32 (m, 2H), 2.69-2.82 (m, 1H), 2.40-2.50 (m,2H), 2.13-2.23 (m, 2H), 1.39-1.90 (m, 10H), 1.13-1.15 (d, 3H). LC-MS:(M−H)+=463.3; HPLC purity=96.95%.

Example 2551-{3-[4-(4-fluorophenyl)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (255)

Synthesis of Compound (255)

Mixture of isomers of (253) separated by using chiral columnchromatography to give Compound (255). 1H NMR (300 MHz, CDCl3): δ 8.21(br s, 1H), 7.34-7.39 (m, 2H), 7.29-7.32 (d, 1H), 7.13-7.17 (d, 1H),7.00-7.06 (m, 3H), 6.81-6.90 (m, 1H), 4.48-4.52 (m, 0.5H), 4.28-4.32 (m,0.5H), 3.24-3.46 (m, 1H), 2.97-3.03 (m, 1H), 2.33-2.67 (m, 3H),1.85-1.90 (m, 2H), 1.41-1.74 (m, 10H), 1.05-1.08 (d, 3H). LC-MS:(M−H)+=463.4; HPLC purity=99.7%; chiral purity=90.74% [column: ChiralpakIC; mobile phase: hexane: IPA: DCM (8.5:1.0:0.5); RT=16.87 min].

Example 2561-{3-[4-(4-fluorophenyl)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (256)

Synthesis of Compound (256)

Mixture of isomers of (253) separated by using chiral columnchromatography to give Compound (256). 1H NMR (300 MHz, DMSO-d6): δ12.15 (br s, 1H), 11.04 (br s, 1H), 7.34-7.44 (m, 3H), 7.16-7.23 (m,3H), 7.06-7.11 (t, 1H), 6.73-6.75 (d, 1H), 4.36-4.40 (m, 0.5H),4.17-4.21 (m, 0.5H), 3.70-3.74 (m, 1H), 3.45-3.48 (m, 1H), 3.04-3.06 (m,1H), 2.73-2.86 (m, 1H), 2.27-2.44 (m, 2H), 2.11-2.19 (m, 1H), 1.35-1.94(m, 10H), 1.20-1.24 (d, 3H). LC-MS: (M−H)+=463.3; HPLC purity=96.51%;chiral purity=89.64% [column: Chiralpak IC; mobile phase:hexane:IPA:DCM(8.5:1.0:0.5); RT=12.92 min].

Example 2571-{3-[4-(2-fluorophenyl)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (257)

Synthesis of Compound (257)

Compound (257) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 8.22 (br s, 1H),7.25-7.35 (m, 3H), 7.03-7.16 (m, 4H), 6.86-6.91 (m, 1H), 4.49-4.51 (m,0.5H), 4.29-4.34 (m, 0.5H), 3.22-3.25 (m, 1H), 2.98-3.05 (m, 1H),2.70-2.78 (m, 1H), 2.36-2.50 (m, 2H), 2.06-2.23 (m, 2H), 1.34-1.75 (m,10H), 1.09-1.11 (d, 3H). LC-MS: (M−H)+=463.3; HPLC purity=94.78%.

Example 2581-[3-(2-cyano-4-cyclopropyl-1-methyl-1H-indol-3-yl)butanoyl]decahydroquinoline-5-carboxylicacid (258)

Synthesis of Compound (258)

Compound (258) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 7.16-7.21 (t,1H), 7.04-7.07 (d, 1H), 6.85-6.87 (d, 1H), 4.70-4.75 (m, 1H), 4.60-4.65(m, 0.1H), 4.37-4.45 (m, 1H), 3.77 (s, 3H), 2.84-3.01 (m, 2H), 2.46-2.55(m, 2H), 2.09-2.27 (m, 2H), 1.47-1.80 (m, 10H), 1.40-1.43 (d, 3H).0.97-1.00 (m, 2H), 0.76-0.79 (m, 2H). LC-MS: (M−H)+=448.4; HPLCpurity=99.99%.

Example 2591-{3-[4-(3-fluorophenyl)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (259)

Synthesis of Compound (259)

Compound (259) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 8.50 (br s, 1H),7.27-7.30 (m, 2H), 7.07-7.15 (m, 3H), 6.97-6.99 (m, 2H), 6.84-6.87 (m,1H), 4.46-4.47 (m, 0.5H), 4.21-4.25 (m, 0.5H), 3.12-3.14 (m, 1H),3.02-3.05 (m, 1H), 2.51-2.57 (m, 2H), 2.35-2.39 (m, 2H), 1.37-1.72 (m,10H), 1.09-1.11 (d, 3H). LC-MS: (M−H)+=463.3; HPLC purity=95.6%.

Example 2601-{[(4-cyclopropyl-1H-indol-3-yl)sulfanyl]acetyl}decahydroquinoline-5-carboxylicacid (260)

Synthesis of Compound (260)

Compound (260) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 8.33 (br s, 1H),7.26-7.36 (m, 1H), 7.09-7.12 (m, 1H), 7.01-7.07 (m, 1H), 6.59-6.62 (d,1H), 4.57-4.61 (m, 0.5H), 4.41-4.46 (m, 0.5H), 3.99-4.08 (m, 1H),3.50-3.66 (m, 2H), 3.19-3.26 (m, 1H), 2.24-2.31 (m, 1H), 2.16-2.21 (m,1H), 1.92-1.94 (m, 1H), 1.35-1.74 (m, 10H), 1.00-1.03 (m, 2H), 0.74-0.77(m, 2H). LC-MS: (M−H)+=413.3; HPLC purity=99.65%.

Example 2611-[3-(4-chloro-1-cyclopropyl-1H-indol-3-yl)butanoyl]decahydroquinoline-5-carboxylicacid (261)

Synthesis of Compound (261)

Compound (261) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 7.36-7.38 (m,1H), 6.96-7.02 (m, 3H), 4.62-4.68 (0.5H), 4.20-4.26 (m, 0.5H), 3.95-4.10(m, 1H), 3.62-3.68 (m, 1H), 3.20-3.22 (m, 1H), 2.83-2.89 (m, 1H),2.51-2.58 (m, 3H), 2.19-2.23 (m, 1H), 1.38-1.79 (m, 10H), 1.34-1.36 (d,3H), 0.98-1.00 (m, 2H), 0.91-0.92 (m, 2H). LC-MS: (M−H)+=443.3; HPLCpurity=97.77%.

Example 2621-{3-[4-(3-fluoropyridin-2-yl)-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (262)

Synthesis of Compound (262)

Compound (262) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 12.01 (br s,1H), 11.09 (br s, 1H), 8.45 (s, 1H), 7.72-7.81 (m, 1H), 7.47-0.50 (m,2H), 7.24 (s, 1H), 7.12-7.17 (t, 1H), 6.88-6.90 (d, 1H), 4.14-4.38 (m,0.5H), 3.70-3.78 (m, 0.5H), 3.40-3.48 (m, 2H), 2.72-2.78 (m, 2H),2.30-2.35 (m, 1H), 2.22-2.26 (m, 1H), 1.91-2.05 (m, 1H), 1.33-1.70 (m,10H), 1.13-1.17 (d, 3H). LC-MS: (M−H)+=464.3; HPLC purity=95.01%.

Example 2631-{3-[4-(5-fluorofuran-2-yl)-1-methyl-1H-indol-3-yl]butanoyl}decahydroquinoline-5-carboxylicacid (263)

Synthesis of Compound (263)

Compound (263) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 7.26-7.29 (m,1H), 7.12-7.15 (d, 1H), 7.05-7.07 (m, 1H), 6.95 (br s, 1H), 6.28-6.30(m, 1H), 5.45-5.47 (m, 1H), 4.61-4.65 (m, 0.5H), 4.49-4.43 (m, 0.5H),3.72 (s, 3H), 3.43-3.51 (m, 2H), 2.54-2.58 (m, 2H), 2.27-2.30 (m, 1H),2.21-2.24 (m, 1H), 2.05-2.10 (m, 1H), 1.49-1.85 (m, 10H), 1.33-1.36 (d,3H). LC-MS: (M−H)+=467.4; HPLC purity=98.0%.

Example 2641-[3-(4-methoxy-1H-indol-3-yl)butanoyl]decahydroquinoline-5-carboxylicacid (264)

Synthesis of Compound (264)

Compound (264) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 12.13 (br s,1H), 10.76 (br s, 1H), 6.95-6.98 (m, 2H), 6.92-6.93 (d, 1H), 6.43-6.46(d, 1H), 4.52-4.56 (m, 0.5H), 4.30-4.34 (m, 0.5H), 3.82 (s, 3H),3.61-3.63 (m, 2H), 2.96-3.05 (m, 1H), 2.74-2.90 (m, 2H), 2.16-2.39 (m,1H), 1.44-1.90 (m, 10H), 1.37-1.40 (d, 3H). LC-MS: (M−H)+=399.2; HPLCpurity=94.44%.

Example 2651-[4,4,4-trifluoro-3-hydroxy-3-(1H-Indol-3-yl)butanoyl]-decahydroquinoline-5-carboxylicacid (265)

Synthesis of Intermediate-126

To a stirred solution of Starting Material-1 (3.0 g, 25.6 mmol) intoluene (50 mL), Montmorillonite K 10 (15 g) was added and heated at 80°C. for 4 hours. After completion of the reaction (LC-MS), catalyst wasfiltered through the sintered funnel, the filtrate diluted with H₂O andextracted with EtOAc and concentrated to give crude Intermediate 126 (5g), which was taken for next step without any purification.

Synthesis of Intermediate-127

Intermediate-127 was synthesized by following the procedure used to makeIntermediate-3 (Scheme 1).

Synthesis of Intermediate-128

Intermediate-128 was synthesized by following the procedure used to makeCompound-1 (Scheme 2).

Synthesis of Compound (265)

Compound (265) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, CDCl3): δ 8.25 (br s, 1H),7.70-7.80 (m, 1H), 7.33-7.39 (m, 2H), 7.17-7.22 (m, 1H), 7.11-7.16 (m,1H), 4.54-4.58 (m, 0.5H), 4.37-4.41 (m, 0.5H), 3.50-3.75 (m, 1H),3.37-3.45 (d, 1H), 3.04-3.13 (d, 1H), 2.50-2.61 (m, 2H), 2.29-2.31 (m,1H), 1.43-1.90 (m, 10H). LC-MS: (M−H)+=439.2; HPLC purity=93.26%.

Example 2661-[3-(4-chloro-1-ethyl-1H-indol-3-yl)butanoyl]decahydroquinoline-5-carboxylicacid (266)

Synthesis of Compound (266)

Compound (266) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). 1H NMR (300 MHz, DMSO-d6): δ 12.10 (br s,1H), 7.39-7.42 (d, 3H), 7.33-7.36 (d, 3H), 7.05-7.10 (t, 1H), 7.01-7.02(m, 1H), 4.46-4.48 (m, 0.5H), 4.27-4.29 (m, 0.5H), 4.13-4.18 (m, 2H),3.96-3.98 (m, 1H), 3.70-3.72 (m, 1H), 1.14-1.20 (m, 2H), 2.62-2.75 (m,2H), 2.00-2.05 (m, 1H), 1.45-1.80 (m, 10H), 1.26-1.32 (m, 6H). LC-MS:(M−H)+=431.3; HPLC purity=95.81%.

Example 2671-(2-(4-cyclopropyl-1H-indol-3-yl)propanoyl)decahydroquinoline-5-carboxylicacid (267)

Synthesis of Intermediate 129

To a stirred solution of Starting Material-35 (40 g, 206 mmol) in ether(400 mL), oxalyl chloride (23.2 mL, 268 mmol) was added at 0° C., andstirred at room temperature for 5 hours. The reaction mixture was thenfiltered and washed with ether to get solid material (42 g), which wastreated with MeOH (28 mL) in ether (200 mL) at 0° C. to room temperaturefor 5 hours. After completion of the reaction, the reaction mixture wasdiluted with hexanes, resulted precipitate was filtered and dried to getIntermediate-129 (35 g) as yellow solid.

Synthesis of Intermediate-130

To a stirred solution of Intermediate-129 (35 g, 129 mmol) in MeOH (350mL), tosyl hydrazine (23.1 g, 129 mmol) was added and refluxed for 4hours. After completion of the reaction, the reaction mixture wasconcentrated to give crude mixture, which was diluted with H₂O,extracted with DCM and concentrated to give Intermediate-130 (35 g) aspale yellow solid.

Synthesis of Intermediate-131

To a stirred solution of Intermediate-131 (14 g, 31 mmol) in THF (140mL), NaBH₄ (1.8 g, 46 mmol) was added at 0° C. and continued to stir atroom temperature for 6 hours. After completion of the reaction, thereaction mixture was quenched with H₂O, extracted with DCM andconcentrated. The resulted crude product was purified by using silicagel column chromatography elusive with mixture of hexanes, EtOAc to giveIntermediate-131 (3 g) as pale yellow liquid.

Synthesis of Intermediate-132

Intermediate-132 was synthesized by following the procedure used to makeIntermediate-95 (Scheme 56).

Synthesis of Intermediate-133

Intermediate-133 was synthesized by following the procedure used to makeIntermediate-72 (Scheme 47).

Synthesis of Intermediate-134

Intermediate-134 was synthesized by following the procedure used to makeIntermediate-5 (Scheme 3).

Synthesis of Intermediate-135

Intermediate-135 was synthesized by following the procedure used to makeIntermediate-3 (Scheme 1).

Synthesis of Intermediate-136

Intermediate-136 was synthesized by following the procedure used to makeIntermediate-75 (Scheme 47).

Synthesis of Compound (267)

Compound (267) was synthesized by following the procedure used to makeCompound (105) (Scheme 51). LC-MS: (M−H)+=395.3; HPLC purity=94.32%.

Example 268 1-(3-(4-cyclopropyl-1-methyl-1H-indazol-3-yl)propanoyl)decahydroquinoline-5-carboxylic acid (268)

Synthesis of Compound (268)

Compound (268) was synthesized by following the procedure used to makeCompound (88) (Scheme 47). LC-MS: (M−H)+=410.2.

Biological Activity

In Vitro HSD11β1 Inhibition Assay:

CHO cells were maintained in Dulbecco's modified Eagle's medium/nutrientmixture F-12 containing 5% fetal bovine serum (v/v) and 2 mM glutamine.Cells were cultured at 37° C. with 5% CO₂. For transient expression ofhuman full length HSD11 β 1 expression vector (OriGene Technologies),cells were seeded at a density of 2×105 cells/well in a 6-well plate.Transfection was done using Turbofectin8 reagent (OriGene Technologies),according to the protocol provided with the reagent. After 24 hourspost-transfection, cells were trypsinized and pooled together beforethey were re-seeding to 96-well plate at a density of 40000 cells/well.24 hours after re-seeding, cells were incubated with 200 nMcortisone+500 uM NADPH (or along with small molecule inhibitors)overnight. The enzymatic activity or inhibition of enzyme activity wasmeasured by estimating the conversion of cortisone to cortisol byLC/MS-MS method. The IC50 in nM was calculated from an 8 point log scaleof concentration versus inhibition.

The results of the biological testing are shown in table 1:

TABLE 1 11βHSD1 Cmpd No (IC50) 1 ***** 2 * 3 *** 4 **** 5 ***** 6 ** 7 *8 **** 9 ** 10 **** 11 **** 12 * 13 ***** 14 * 15 **** 16 *** 17 *****18 * 19 * 20 ***** 21 * 22 * 23 * 24 * 25 * 26 * 27 ***** 28 **** 29 *30 * 31 * 32 * 33 * 34 * 35 ***** 36 * 37 * 38 *** 39 * 40 * 41 ****42 * 43 * 44 ***** 45 * 46 * 47 ***** 48 * 49 * 50 * 51 * 52 * 53 *****54 * 55 ***** 56 *** 57 * 58 * 59 *** 60 ***** 61 * 62 * 63 * 64 ***65 * 66 ***** 67 * 68 * 69 * 70 * 71 *** 72 ***** 73 * 74 * 75 *****76 * 77 * 78 ***** 79 * 80 * 81 ***** 82 * 83 * 84 ***** 85 * 86 *****87 ***** 88 * 89 *** 90 **** 91 * 92 **** 93 ***** 94 *** 95 ***** 96 *97 *** 98 * 99 * 100 * 101 * 102 * 103 * 104 * 105 * 106 * 107 * 108 *109 * 110 * 111 ***** 112 ***** 113 * 114 ***** 115 * 116 * 117 *****118 ***** 119 ***** 120 ***** 121 ***** 122 ***** 123 ***** 124 **** 125***** 126 * 127 * 128 * 129 * 130 * 131 * 132 *** 133 * 134 * 135 *136 * 137 **** 138 *** 139 **** 140 ***** 141 * 142 ***** 143 *****144 * 145 ***** 146 * 147 * 148 * 149 * 150 **** 151 **** 152 * 153 ***154 * 155 * 156 ***** 157 ***** 158 * 159 ***** 160 * 161 ***** 162 *163 * 164 **** 165 * 166 * 167 ***** 168 * 169 * 170 * 171 * 172 * 173***** 174 * 175 * 176 *** 177 *** 178 * 179 * 180 * 181 * 182 * 183 *184 * 185 *** 186 ***** 187 * 188 ***** 189 * 190 ***** 191 **** 192***** 193 **** 194 * 195 ***** 196 ***** 197 * 198 **** 199 ***** 200***** 201 ***** 202 * 203 * 204 ***** 205 * 206 ***** 207 * 208 **** 209*** 210 **** 211 ***** 212 * 213 * 214 ***** 215 ***** 216 ***** 217**** 218 ***** 219 * 220 ***** 221 ***** 222 **** 223 **** 224 ***** 225***** 226 * 227 * 228 * 229 **** 230 *** 231 *** 232 *** 233 * 234 * 235***** 236 **** 237 *** 238 * 239 * 240 * 241 * 242 * 243 ***** 244 * 245***** 246 * 247 * 248 ***** 249 ** 250 ***** 251 ***** 252 * 253 *****254 * 255 ***** 256 * 257 **** 258 * 259 *** 260 * 261 ** 262 * 263***** 264 * 265 * 266 * 267 * 268 * ***** = <100 nM **** = 100 nM< and<150 nM *** = 150 nM< and <200 nM ** = 200 nM< and <250 nM * = 250 nM<

The invention claimed is:
 1. A compound of formula (I):

wherein: each R¹ and R^(1a) is independently selected from the groupconsisting of H, methyl, CONHC(CH₃)₃, OH, CO₂H, CO₂CH₃, CO₂CH₂CH₃,phenyl, CH₂OH, CN, tetrazole and OCH₃, or any two R¹ on adjacent carbonatoms may be joined to form a cyclic moiety, or any two R¹ on the samecarbon when taken together may form a group of the formula ═O, Ar is anoptionally substituted C₁-C₁₈heteroaryl group selected from the groupconsisting of:

wherein each R⁷ is independently selected from the group consisting ofH, halogen, OH, NO₂, CN, SH, NH₂, CF₃, OCF₃, C₁-C₁₂alkyl,C₁-C₁₂haloalkyl, C₂-C₁₂alkenyl, C₂-C₁₂alkynyl, C₂-C₁₂heteroalkyl,C₃-C₁₂cycloalkyl, C₃-C₁₂cycloalkenyl, C₂-C₁₂heterocycloalkyl,C₂-C₁₂heterocycloalkenyl, C₆-C₁₈aryl, C₁-C₁₈heteroaryl, C₁-C₁₂alkyloxy,C₂-C₁₂alkenyloxy, C₂-C₁₂alkynyloxy, C₂-C₁₀heteroalkyloxy,C₃-C₁₂cycloalkyloxy, C₃-C₁₂cycloalkenyloxy, C₂-C₁₂heterocycloalkyloxy,C₂-C₁₂ heterocycloalkenyloxy, C₆-C₁₈aryloxy, C₁-C₁ heteroaryloxy,C₁-C₁₂alkylamino, SR⁹, SO₃H, SO₂NR⁹R¹⁰, SO₂R⁹, SONR⁹R¹⁰, SOR⁹, COR⁹,COOH, COOR⁹, CONR⁹R¹⁰, NR⁹COR¹⁰, NR⁹COOR¹⁰, NR⁹SO₂R¹⁰, NR⁹CONR⁹R¹⁰,NR⁹R¹⁰, and acyl; wherein R⁸ is selected from the group consisting of H,C₁-C₁₂alkyl, C₂-C₁₂alkenyl, C₂-C₁₂alkynyl, C₂-C₁₂heteroalkyl,C₃-C₁₂cycloalkyl, C₂-C₁₂heterocycloalkyl, C₆-C₁₈aryl, C₁-C₁₈heteroaryl,SO₃H, SO₂NR⁹R¹⁰, SO₂R⁹, SONR⁹R¹⁰, SOR⁹, COR⁹, COOH, COOR⁹, and CONR⁹R¹⁰;wherein each R⁹ and R¹⁰ is independently selected from the groupconsisting of H, C₁-C₁₂alkyl, C₂-C₁₀heteroalkyl, C₁-C₁₂haloalkyl,C₃-C₁₂cycloalkyl, C₆-C₁₈aryl, and C₁-C₁₈heteroaryl; e is an integerselected from the group consisting of 0, 1, 2, 3 and 4; f is an integerselected the group consisting of 0, 1, 2, and 3; A is —CR^(a)R^(b)—; Bis CH₂; wherein each R^(a) and R^(b), is independently selected from thegroup consisting of H, halogen, OH, NO₂, CN, SH, NH₂, CF₃, OCF₃,C₁-C₁₂alkyl, C₂-C₁₀heteroalkyl, C₁-C₁₂haloalkyl, C₃-C₁₂cycloalkyl,C₆-C₁₈aryl, C₁-C₁₈heteroaryl; SR², SO₃H, SO₂NR²R³, SO₂R², SONR²R³, SOR²,COR², COOH, COOR², CONR²R³, NR²COR³, NR²COOR³, NR²SO₂R³, NR²CONR²R²,NR²R³, and acyl and further wherein R^(a) and R^(b) are different;wherein each R² and R³ is independently selected from the groupconsisting of H, C₁-C₁₂alkyl, C₂-C₁₀heteroalkyl, C₁-C₁₂haloalkyl,C₃-C₁₂cycloalkyl, C₆-C₁₈aryl, and C₁-C₁₈heteroaryl; W¹ and W² areselected such that one is N and the other is (CR¹ ₂), the bond from thecarbonyl carbon is joined to whichever of W¹ or W² is N, D is (CR¹ ₂), nis an integer selected from the group consisting of 0, 1, and 2; a is aninteger selected from the group consisting of 0, 1, 2, and 3; b is aninteger selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7,and 8, c is 1; or a pharmaceutically acceptable salt thereof.
 2. Acompound according to claim 1 having the formula:

wherein Ar, R^(a), R^(b), R¹, R^(1a), a and b are as defined in claim 1.3. A compound according to claim 2 wherein one of R^(a) and R^(b) is Hand the other is optionally substituted alkyl.
 4. A compound accordingto claim 1 wherein the R⁷ substituent is located in the 4 or the 5position of the six membered ring.
 5. A compound according to claim 1wherein R⁷ is selected from the group consisting of CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, (CH₂)₃CH₃, Cl, Br, F, I, OH, NO₂, NH₂, CN, SO₃H,OCH₃, OCH₂CH₂CH₃, CF₃, and OCF₃.
 6. A compound according to claim 1selected from the group consisting of:

or pharmaceutically acceptable salt thereof.
 7. A pharmaceuticalcomposition including a compound according to claim 1 and apharmaceutically acceptable diluent, excipient or carrier.
 8. A methodof treatment of a condition selected from the group consisting of Type Idiabetes, Type II diabetes, hyperglycemia, low glucose tolerance,hyperinsulinemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia, obesity, abdominal obesity,glaucoma, hypertension, atherosclerosis and its sequelae, retinopathy,nephropathy, neuropathy, osteoporosis, osteoarthritis, dementia,depression, psychiatric disorders, Cushing's Disease, and Cushing'ssyndrome, in a mammal, the method comprising administering an effectiveamount of a compound according to claim
 1. 9. A method according toclaim 8 wherein the condition is type II diabetes.
 10. The method ofclaim 8, wherein the compound is administered in combination with anadjuvant.
 11. The method of claim 10, wherein the adjuvant is selectedfrom the group consisting of dipeptidyl peptidase-IV (DP-IV) inhibitors;(b) insulin sensitizing agents; (c) insulin and insulin mimetics; (d)sulfonylureas and other insulin secretagogues; (e) alpha-glucosidaseinhibitors; (f) GLP-1, GLP-1 analogs, and GLP-1 receptor agonists; andcombinations thereof.
 12. The method of claim 11, wherein the insulinsensitizing agents are selected from the group consisting of (i)PPAR-gamma-agonists, (ii) PPAR-alpha-agonists, (iii)PPAR-alpha/gamma-dual agonists, (iv) biguanides, and combinationsthereof.
 13. A pharmaceutical composition including a compound accordingto claim 6 and a pharmaceutically acceptable diluent, excipient orcarrier.
 14. A method of treatment of a condition selected from thegroup consisting of Type I diabetes, Type II diabetes, hyperglycemia,low glucose tolerance, hyperinsulinemia, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, dyslipidemia, obesity,abdominal obesity, glaucoma, hypertension, atherosclerosis and itssequelae, retinopathy, nephropathy, neuropathy, osteoporosis,osteoarthritis, dementia, depression, psychiatric disorders, Cushing'sDisease, and Cushing's syndrome, in a mammal, the method comprisingadministering an effective amount of a compound according to claim 6.15. A method according to claim 6 wherein the condition is type IIdiabetes.
 16. The method of claim 6, wherein the compound isadministered in combination with an adjuvant.
 17. The method of claim 6,wherein the adjuvant is selected from the group consisting of dipeptidylpeptidase-IV (DP-IV) inhibitors; (b) insulin sensitizing agents; (c)insulin and insulin mimetics; (d) sulfonylureas and other insulinsecretagogues; (e) alpha-glucosidase inhibitors; (f) GLP-1, GLP-1analogs, and GLP-1 receptor agonists; and combinations thereof.
 18. Themethod of claim 6, wherein the insulin sensitizing agents are selectedfrom the group consisting of (i) PPAR-gamma-agonists, (ii)PPAR-alpha-agonists, (iii) PPAR-alpha/gamma-dual agonists, (iv)biguanides, and combinations thereof.